1,436 results on '"protein structures"'
Search Results
152. The Role of Protein Structural Analysis in the Next Generation Sequencing Era
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Yue, Wyatt W., Froese, D. Sean, Brennan, Paul E., Houk, Kendall N., Series editor, Hunter, Christopher A., Series editor, Krische, Michael J, Series editor, Lehn, Jean-Marie, Series editor, Ley, Steven V., Series editor, Olivucci, Massimo, Series editor, Thiem, Joachim, Series editor, Venturi, Margherita, Series editor, Wong, Chi-Huey, Series editor, Wong, Henry N.C., Series editor, L.S. Tang, Nelson, editor, and Poon, Terence, editor
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- 2014
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153. The Hunt for the Closed Conformation of the Fruit‐Ripening Enzyme 1‐Aminocyclopropane‐1‐carboxylic Oxidase: A Combined Electron Paramagnetic Resonance and Molecular Dynamics Study.
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Fournier, Eugénie, Tachon, Sybille, Fowler, Nicholas J., Gerbaud, Guillaume, Mansuelle, Pascal, Dorlet, Pierre, Visser, Sam P., Belle, Valérie, Simaan, A. Jalila, and Martinho, Marlène
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ELECTRON paramagnetic resonance , *MOLECULAR dynamics , *ELECTRON paramagnetic resonance spectroscopy , *NITROXIDES , *FLOWERING of plants , *DIOXYGENASES , *OXIDASES - Abstract
1‐Aminocyclopropane‐1‐carboxylic oxidase (ACCO) is a non‐heme iron(II)‐containing enzyme involved in the biosynthesis of the phytohormone ethylene, which regulates fruit ripening and flowering in plants. The active conformation of ACCO, and in particular that of the C‐terminal part, remains unclear and open and closed conformations have been proposed. In this work, a combined experimental and computational study to understand the conformation and dynamics of the C‐terminal part is reported. Site‐directed spin‐labeling coupled to electron paramagnetic resonance (SDSL‐EPR) spectroscopy was used. Mutagenesis experiments were performed to generate active enzymes bearing two paramagnetic labels (nitroxide radicals) anchored on cysteine residues, one in the main core and one in the C‐terminal part. Inter‐spin distance distributions were measured by pulsed EPR spectroscopy and compared with the results of molecular dynamics simulations. The results reveal the existence of a flexibility of the C‐terminal part. This flexibility generates several conformations of the C‐terminal part of ACCO that correspond neither to the existing crystal structures nor to the modelled structures. This highly dynamic region of ACCO raises questions on its exact function during enzymatic activity. [ABSTRACT FROM AUTHOR]
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- 2019
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154. ACMS: a database of alternate conformations found in the atoms of main and side chains of protein structures.
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Santhosh, R., Chandrasekaran, P., Michael, Daliah, Rangachari, K., Bankoti, Namrata, Jeyakanthan, J., and Sekar, K.
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PROTEIN structure , *PROTEIN conformation , *ATOMS , *BIOMACROMOLECULES , *KNOWLEDGE base - Abstract
Proteins are usually dynamic biological macromolecules, thereby exhibiting a large number of conformational ensembles which influence the association with their neighbours and interacting partners. Most of the side‐chain atoms and a few main‐chain atoms of the high‐resolution crystal structures deposited in the Protein Data Bank adopt alternate conformations. This kind of conformational behaviour prompted the authors to explore the relationship, if any, between the alternate conformations and the function of the protein molecule. Thus, a knowledge base of the alternate conformations of the main‐ and side‐chain atoms of protein structures has been developed. It provides a detailed description of the alternate conformations of various residues for more than 60 000 high‐resolution crystal structures. The proposed knowledge base is very user friendly and has various flexible options. The knowledge base will be updated periodically and can be accessed at http://iris.physics.iisc.ac.in/acms. [ABSTRACT FROM AUTHOR]
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- 2019
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155. Effect of the disruption chamber geometry on the physicochemical and structural properties of water-soluble myofibrillar proteins prepared by high pressure homogenization (HPH).
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Li, Yufeng, Chen, Xing, Xue, Siwen, Li, Ming, Xu, Xinglian, Han, Minyi, and Zhou, Guanghong
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PROTEINS , *PRESSURE - Abstract
Abstract High pressure homogenization (HPH) can solubilize myofibrillar proteins (MPs) in water. To elucidate the effect of the HPH disruption chamber geometry on the physicochemical and structural properties of MPs in water, two types of nozzle and a counter flow interaction chamber (cf) were applied to homogenize MPs aqueous solutions at pressures of 0 MPa, 103 MPa and 172 MPa HPH for 2 passes, and the physical dispersion and conformational characteristics of MPs in water were investigated. The nozzles and counter flow chamber played a major role in the solubility of MPs in water at 103 MPa and 172 MPa HPH, respectively. Turbulence and cavitation in a narrow nozzle and counter flow action resulted in a decreased MP particle size (232 nm) in water, destroyed secondary structures and exposed hydrophobic and SH groups. The solubility (98.1%) and stability of MPs in water were increased by HPH. The results showed that the required solubility of MPs in water can be achieved by adopting proper HPH disruption chamber geometry , which provides a new method on meat processing. Highlights • High pressure homogenization (HPH) solubilized myofibrillar proteins (MPs) in water. • HPH at 172 MPa induced a better solubility and stability of MPs in water. • The bore diameter of nozzle played a major role at 103 MPa HPH. • At 172 MPa HPH, the counter flow interaction chamber was dominant. [ABSTRACT FROM AUTHOR]
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- 2019
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156. The study of protein conformation and hydration characteristics of meat batters at various phase transition temperatures combined with Low-field nuclear magnetic resonance and Fourier transform infrared spectroscopy.
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Han, Zongyuan, Zhang, Junlong, Zheng, Jinyue, Li, Xiaojing, and Shao, Jun-Hua
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BATTERS (Food) , *PROTEIN conformation , *PROTEIN content of meat , *PHASE transitions , *NUCLEAR magnetic resonance spectroscopy - Abstract
Graphical abstract Highlights • The transition of sol into gel at phase transition temperatures was demonstrated. • At 50 °C, immobilised water was gradually exchanged into free water by Low-field NMR and WHC significantly decreased. • By FT-IR, α-helix significantly decreased and α-helix was transformed into β-sheets. • The relationship between hydration characteristics and protein conformation was established. Abstract To get a thorough understanding of evolution of heat-induced gel in meat batters, water distribution, protein conformation and their chemical bonds at phase transition temperatures (20–74 °C) were investigated by Low-field NMR and FT-IR. Firstly, G ′ increased and tan δ decreased beyond 55 °C, when sol was completely changed into an elastic gel. Then water holding capacity (WHC) decreased along with decreasing relaxation time T 22 and a new relaxation time T 23 appeared at 50 °C, which indicated that partially immobilised water was converted into free water outside. Meanwhile, surface hydrophobicity increased significantly and free sulfhydryl contents decreased, which contributed to the formation of disulfide bonds, especially beyond 55 °C. Finally, the transformation of α-helix into β-sheets occurred, and increasing β-sheets are necessary for the formation of elastic gels. Moreover, there was a significant correlation between α-helical contents and water loss, surface hydrophobicity, sulfhydryl contents. [ABSTRACT FROM AUTHOR]
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- 2019
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157. High Accuracy Protein Structures from Minimal Sparse Paramagnetic Solid‐State NMR Restraints.
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Perez, Alberto, Gaalswyk, Kari, Jaroniec, Christopher P., and MacCallum, Justin L.
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PROTEIN structure , *PROTEIN models , *ACCURACY , *PARAMAGNETIC materials , *NUCLEAR magnetic resonance spectroscopy , *DATA mapping - Abstract
There is a pressing need for new computational tools to integrate data from diverse experimental approaches in structural biology. We present a strategy that combines sparse paramagnetic solid‐state NMR restraints with physics‐based atomistic simulations. Our approach explicitly accounts for uncertainty in the interpretation of experimental data through the use of a semi‐quantitative mapping between the data and the restraint energy that is calibrated by extensive simulations. We apply our approach to solid‐state NMR data for the model protein GB1 labeled with Cu2+‐EDTA at six different sites. We are able to determine the structure to 0.9 Å accuracy within a single day of computation on a GPU cluster. We further show that in some cases, the data from only a single paramagnetic tag are sufficient for accurate folding. [ABSTRACT FROM AUTHOR]
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- 2019
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158. A minimum set of stable blocks for rational design of polypeptide chains.
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Nekrasov, Alexei N., Alekseeva, Ludmila G., Pogosyan, Rudolf А., Dolgikh, Dmitry A., Kirpichnikov, M.P., de Brevern, Alexandre G., and Anashkina, Anastasia A.
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MOLECULAR dynamics , *PROTEIN conformation , *MOLECULAR structure , *PROTEIN structure , *AMINO acid sequence , *FUNCTIONAL groups - Abstract
The aim of this work was to find a minimal set of structurally stable pentapeptides, which allows forming a polypeptide chain of a required 3D structure. To search for factors that ensure structural stability of the pentapeptide, we generated peptide sequences with no more than three functional groups, based on the alanine pentapeptide AAAAA. We analyzed 44,860 structures of peptides by the molecular dynamics method and found that 1,225 pentapeptides over 80% of the simulation time were in a stable conformation. Clustering of these conformations revealed 54 topological types of conformationally stable pentapeptides. These conformations relate to different combined elements of the protein secondary structure. So, we obtained a minimal set of amino acid structures of conformationally stable pentapeptides, creating a complete set of different topologies that ensure the formation of pre-folded conformation of protein structures. • Molecular dynamics simulation of more than 3,000,000 different polypeptides. • Definition of a limited set of local conformational patterns adopted by short peptide fragments. • Formation of pre-folded conformation of protein structures. [ABSTRACT FROM AUTHOR]
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- 2019
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159. Infinite Assembly of Folded Proteins in Evolution, Disease, and Engineering.
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Garcia‐Seisdedos, Hector, Villegas, José A., and Levy, Emmanuel D.
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BIOMATERIALS , *PROTEINS , *POTENTIAL well , *BIOLOGICAL evolution , *ETIOLOGY of diseases - Abstract
Mutations and changes in a protein's environment are well known for their potential to induce misfolding and aggregation, including amyloid formation. Alternatively, such perturbations can trigger new interactions that lead to the polymerization of folded proteins. In contrast to aggregation, this process does not require misfolding and, to highlight this difference, we refer to it as agglomeration. This term encompasses the amorphous assembly of folded proteins as well as the polymerization in one, two, or three dimensions. We stress the remarkable potential of symmetric homo‐oligomers to agglomerate even by single surface point mutations, and we review the double‐edged nature of this potential: how aberrant assemblies resulting from agglomeration can lead to disease, but also how agglomeration can serve in cellular adaptation and be exploited for the rational design of novel biomaterials. The term agglomeration encompasses the amorphous assembly of folded proteins as well as their 1D, 2D, or 3D polymerization. Symmetric homo‐oligomers are prone to agglomerate, even through single surface point mutations. This Review summarizes how agglomeration can lead to aberrant assemblies and cause disease, how it can serve in cellular adaptation, and how it can be exploited for the rational design of novel biomaterials. [ABSTRACT FROM AUTHOR]
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- 2019
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160. The Mechanistic Impact of N-Glycosylation on Stability, Pharmacokinetics, and Immunogenicity of Therapeutic Proteins.
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Zhou, Qun and Qiu, Huawei
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GLYCANS , *PROTEINS , *BLOOD proteins , *PHARMACOKINETICS , *RECOMBINANT proteins - Abstract
Abstract N-glycosylation is one of major post-translational modifications in nature, and it is essential for protein structure and function. As hydrophilic moieties of glycoproteins, N-glycans play important roles in protein stability. They protect the proteins against proteolytic degradation, aggregation, and thermal denaturation through maintaining optimal conformations. There are extensive evidences showing the involvement of N-glycans in the pharmacodynamics and pharmacokinetics of recombinant therapeutic proteins and antibodies. Highly sialylated complex-type glycans enable the longer serum half-lives of proteins against uptake through hepatic asialoglycoprotein receptor and mannose receptor for degradation in lysosomes. Moreover, the presence of nonhuman glycans results in clearance through pre-existing antibodies from serum and induces IgE-mediated anaphylaxis. N-glycans also facilitate or reduce the adverse immune responses of the proteins through interacting with multiple glycan-binding proteins, including those specific for mannose or mannose 6-phosphate. Due to the glycan impacts, a few therapeutic proteins were glycoengineered to improve the pharmacokinetics and stability. Thus, N-glycosylation should be extensively investigated and optimized for each individual protein for better efficacy and safety. [ABSTRACT FROM AUTHOR]
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- 2019
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161. Structure‐Activity Relationship of NF023 Derivatives Binding to XIAP‐BIR1.
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Sorrentino, Luca, Cossu, Federica, Milani, Mario, Malkoc, Bilge, Huang, Wen‐Chieh, Tsay, Shwu‐Chen, Ru Hwu, Jih, and Mastrangelo, Eloise
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STRUCTURE-activity relationships , *UBIQUITIN ligases , *PROTEIN-protein interactions , *DIMERIZATION , *MONOMERS , *CANCER cells - Abstract
Inhibitors of Apoptosis Proteins (IAPs) are conserved E3‐ligases that ubiquitylate substrates to prevent apoptosis and activate the NF‐kB survival pathway, often deregulated in cancer. IAPs‐mediated regulation of NF‐kB signaling is based on the formation of protein complexes by their type‐I BIR domains. The XIAP‐BIR1 domain dimerizes to bind two TAB1 monomers, leading to downstream NF‐kB activation. Thus, impairment of XIAP‐BIR1 dimerization could represent a novel strategy to hamper cell survival in cancer. To this aim, we previously reported NF023 as a potential inhibitor of XIAP‐BIR1 dimerization. Here we present a thorough analysis of NF023 binding to XIAP‐BIR1 through biochemical, biophysical and structural data. The results obtained indicate that XIAP‐BIR1 dimerization interface is involved in NF023 binding, and that NF023 overall symmetry and the chemical features of its central moiety are essential for an efficient interaction with the protein. Such strategy provides original hints for the development of novel BIR1‐specific compounds as pro‐apoptotic agents. [ABSTRACT FROM AUTHOR]
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- 2019
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162. Characterization of PEGylated Asparaginase: New Opportunities from NMR Analysis of Large PEGylated Therapeutics.
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Cerofolini, Linda, Giuntini, Stefano, Carlon, Azzurra, Ravera, Enrico, Calderone, Vito, Fragai, Marco, Parigi, Giacomo, and Luchinat, Claudio
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POLYETHYLENE glycol , *CRYSTAL structure , *NANOPARTICLES , *NUCLEAR magnetic resonance , *PROTEINS - Abstract
Resonance assignment and structural characterization of pharmacologically relevant proteins promise to improve understanding and safety of these proteins by rational design. However, the PEG coating that is used to evade the immune system also causes these molecules to "evade" the standard structural biology methodologies. We here demonstrate that it is possible to obtain the resonance assignment and a reliable structural model of large PEGylated proteins through an integrated approach encompassing NMR and X‐ray crystallography. Coating a protein with PEG may have structural consequences, but no single biophysical methodology can spot the possible modifications. This limitation has been overcome by the integration of solution and solid‐state NMR data, relaxometry, and X‐ray crystallography for the characterization of a PEGylated enzyme used in clinical practice. [ABSTRACT FROM AUTHOR]
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- 2019
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163. Noncovalent Complexes Formed between Metal‐Substituted Polyoxometalates and Hen Egg White Lysozyme.
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Vandebroek, Laurens, Mampaey, Yentl, Antonyuk, Svetlana, Van Meervelt, Luc, and Parac‐Vogt, Tatjana N.
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POLYOXOMETALATES , *LYSOZYMES , *CRYSTALLIZATION , *SUBSTITUTION reactions , *CRYSTAL structure , *METAL-organic frameworks - Abstract
Four Wells–Dawson type metal‐substituted polyoxometalates (MSPs), 1:2 ZrIV‐Wells–Dawson [ZrIV(α2‐P2W17O61)]8– (1), 1:1 CoII‐Wells–Dawson [CoII(α2‐P2W17O61)]10– (2), 1:1 NiII‐Wells–Dawson [NiII(α2‐P2W17O61)]10– (3) and 1:1 CuII‐Wells–Dawson [CuII(α2‐P2W17O61)]10– (4), which differ in the nature of the imbedded metal ion, were examined in co‐crystallization experiments with a protein Hen Egg White Lysozyme (HEWL). Single crystal X‐ray structures of four noncovalent complexes between POMs and HEWL have been determined, and the influence of the type of substituted metal on the mode of POM binding to a protein was investigated. All crystal structures exhibited a high degree of similarity, suggesting that the interaction is largely independent on the nature of substituted metal within the same polyoxometalate (POM) archetype. The main driving force for the formation of the noncovalent complex is electrostatic attraction between POM and HEWL surface regions. Stabilization is further provided by direct and water mediated hydrogen bonding between terminal oxygen atoms of the POM framework and flexible HEWL residues. Single crystal X‐ray structures of four noncovalent complexes between POMs and HEWL were determined, and the influence of the type of substituted metal on the mode of POM binding to a protein was investigated. [ABSTRACT FROM AUTHOR]
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- 2019
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164. An overview of Sirtuins as potential therapeutic target: Structure, function and modulators.
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Wang, Yijie, He, Jun, Liao, Mengya, Hu, Mingxing, Li, Wenzhen, Ouyang, Hongling, Wang, Xin, Ye, Tinghong, Zhang, Yiwen, and Ouyang, Liang
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SIRTUINS , *HISTONE acetylation , *DINUCLEOTIDES , *PROTEIN structure , *CARDIOVASCULAR diseases - Abstract
Abstract Sirtuin (Yeast Silent Information RegulatorsⅡ, Sir2) was first discovered in the 1970s. Because of its function by removing acetylated groups from histones in the presence of nicotinamide adenine dinucleotide (NAD+), waves of research have assessed the potential of Sirtuin as a therapeutic target. The Sirtuin family, which is widely distributed throughout the nature, has been divided into seven human isoforms (Sirt1-Sirt7). They are thought to be closely related to some aging diseases such as cardiovascular disorders, neurodegeneration, and tumors. Herein, we present a comprehensive review of the structure, function and modulators of Sirtuins, which is expected to be beneficial to relevant studies. Graphical abstract Image 1 Highlights • The roles of Sirtuins are thoroughly discussed. • The functions of Sirtuins are outlined. • An overview for the modulators of Sirtuins is introduced in detail. [ABSTRACT FROM AUTHOR]
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- 2019
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165. Refinement of Highly Flexible Protein Structures using Simulation‐Guided Spectroscopy.
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Hays, Jennifer M., Kieber, Marissa K., Li, Jason Z., Han, Ji In, Columbus, Linda, and Kasson, Peter M.
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PROTEIN structure , *HYPOTHESIS , *INFORMATION theory , *MOLECULAR dynamics , *PROTEIN folding - Abstract
Highly flexible proteins present a special challenge for structure determination because they are multi‐structured yet not disordered, so their conformational ensembles are essential for understanding function. Because spectroscopic measurements of multiple conformational populations often provide sparse data, experiment selection is a limiting factor in conformational refinement. A molecular simulations‐ and information‐theory based approach to select which experiments best refine conformational ensembles has been developed. This approach was tested on three flexible proteins. For proteins where a clear mechanistic hypothesis exists, experiments that test this hypothesis were systematically identified. When available data did not yield such mechanistic hypotheses, experiments that significantly outperform structure‐guided approaches in conformational refinement were identified. This approach offers a particular advantage when refining challenging, underdetermined protein conformational ensembles. Molecular‐dynamics‐aided spectroscopy: A method for guiding spectroscopic experiment selection that permits efficient refinement of protein conformational ensembles has been developed. This method employs molecular dynamics simulation and information theory and is tested via DEER spectroscopy. [ABSTRACT FROM AUTHOR]
- Published
- 2018
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166. Fast Magic‐Angle Spinning 19F NMR Spectroscopy of HIV‐1 Capsid Protein Assemblies.
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Wang, Mingzhang, Lu, Manman, Fritz, Matthew P., Quinn, Caitlin M., Byeon, In‐Ja L., Byeon, Chang‐Hyeock, Struppe, Jochem, Maas, Werner, Gronenborn, Angela M., and Polenova, Tatyana
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NUCLEAR magnetic resonance spectroscopy , *CAPSIDS , *PHARMACEUTICAL chemistry , *TRYPTOPHAN , *STRUCTURAL analysis (Engineering) - Abstract
19F NMR spectroscopy is an attractive and growing area of research with broad applications in biochemistry, chemical biology, medicinal chemistry, and materials science. We have explored fast magic angle spinning (MAS) 19F solid‐state NMR spectroscopy in assemblies of HIV‐1 capsid protein. Tryptophan residues with fluorine substitution at the 5‐position of the indole ring were used as the reporters. The 19F chemical shifts for the five tryptophan residues are distinct, reflecting differences in their local environment. Spin‐diffusion and radio‐frequency‐driven‐recoupling experiments were performed at MAS frequencies of 35 kHz and 40–60 kHz, respectively. Fast MAS frequencies of 40–60 kHz are essential for consistently establishing 19F–19F correlations, yielding interatomic distances of the order of 20 Å. Our results demonstrate the potential of fast MAS 19F NMR spectroscopy for structural analysis in large biological assemblies. Think big: The structural characterization of large biological systems is a challenge by conventional techniques. Fast MAS 19F NMR spectroscopy was found to be an attractive means for investigating protein assemblies (see picture). In the investigation of HIV‐1 capsid protein assemblies, high spectral resolution was attained in 19F–19F correlation spectra, permitting the detection of nanometer distances of the order of 20 Å. [ABSTRACT FROM AUTHOR]
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- 2018
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167. How [Fe]‐Hydrogenase from Methanothermobacter is Protected Against Light and Oxidative Stress.
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Wagner, Tristan, Huang, Gangfeng, Ermler, Ulrich, and Shima, Seigo
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METHANOTHERMOBACTER , *OXIDATIVE stress , *HYDROGENASE , *OLIGOMERIZATION , *ENZYMES - Abstract
[Fe]‐hydrogenase (Hmd) catalyzes the reversible hydrogenation of methenyltetrahydromethanopterin (methenyl‐H4MPT+) with H2. Hmd contains the iron–guanylylpyridinol (FeGP) cofactor, which is sensitive to light and oxidative stress. A natural protection mechanism is reported for Hmd based on structural and biophysical data. Hmd from Methanothermobacter marburgensis (mHmd) was found in a hexameric state, where an expanded oligomerization loop is detached from the dimer core and intrudes into the active site of a neighboring dimer. An aspartic acid residue from the loop ligates to FeII of the FeGP cofactor and thus blocks the postulated H2‐binding site. In solution, this enzyme is in a hexamer‐to‐dimer equilibrium. Lower enzyme concentrations, and the presence of methenyl‐H4MPT+, shift the equilibrium toward the active dimer side. At higher enzyme concentrations—as present in the cell—the enzyme is predominantly in the inactive hexameric state and is thereby protected against light and oxidative stress. [Fe]‐hydrogenase (Hmd) contains the iron–guanylylpyridinol (FeGP) cofactor, which is sensitive to UV‐A/blue light and H2O2. In hexameric Hmd from Methanothermobacter marburgensis (mHmd), an expanded loop is detached from the dimer core and intrudes into the active site of a neighboring dimer. An aspartic acid (Asp) residue from the loop ligates to the Fe center. In the hexameric form, mHmd is protected against light and oxidative stress. [ABSTRACT FROM AUTHOR]
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- 2018
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168. S⋅⋅⋅Sn Tetrel Bonds in the Activation of Peroxisome Proliferator‐Activated Receptors (PPARs) by Organotin Molecules.
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Frontera, Antonio and Bauzá, Antonio
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PEROXISOME proliferator-activated receptors , *HYDROGEN bonding , *ORGANOTIN compounds , *METHIONINE , *MOLECULES , *MOLECULAR structure - Abstract
In this study, a PDB (Protein Data Bank) analysis and theoretical calculations (PBE0‐D3/def2‐TZVP level of theory) were combined to analyze the impact of S⋅⋅⋅Sn tetrel‐bonding interactions in the activation mechanism of peroxisome proliferator‐activated receptors (PPARs) by two organotin derivatives, triphenyltin (TPT) and tributyltin (TBT). The presence of a covalently bonded CYS285 to the organotin molecule was found to be key to enhance the σ‐hole‐donor ability of the tin atom, thus strengthening the tetrel‐bonding interaction with a sulfur atom belonging to a vicinal methionine residue (MET364). Tetrel bonds in action: A combined Protein Data Bank and computational analysis (PBE0‐D3/def2‐TZVP) revealed the importance of S⋅⋅⋅Sn tetrel‐bonding interactions in the mechanism of activation of peroxisome proliferator‐activated receptors (PPARs) by organotin molecules. [ABSTRACT FROM AUTHOR]
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- 2018
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169. Modeling conformational states of proteins with AlphaFold.
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Sala, D., Engelberger, F., Mchaourab, H.S., and Meiler, J.
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PROTEIN structure , *MACHINE learning , *PROTEINS - Abstract
Many proteins exert their function by switching among different structures. Knowing the conformational ensembles affiliated with these states is critical to elucidate key mechanistic aspects that govern protein function. While experimental determination efforts are still bottlenecked by cost, time, and technical challenges, the machine-learning technology AlphaFold showed near experimental accuracy in predicting the three-dimensional structure of monomeric proteins. However, an AlphaFold ensemble of models usually represents a single conformational state with minimal structural heterogeneity. Consequently, several pipelines have been proposed to either expand the structural breadth of an ensemble or bias the prediction toward a desired conformational state. Here, we analyze how those pipelines work, what they can and cannot predict, and future directions. [ABSTRACT FROM AUTHOR]
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- 2023
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170. Possible dynamic roles for the electrostatic force in biological membrane systems
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Berry, Richard M.
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572 ,Protein structures - Published
- 1992
171. Crystal structure of CmABCB1 multi-drug exporter in lipidic mesophase revealed by LCP-SFX
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Dongqing Pan, Ryo Oyama, Tomomi Sato, Takanori Nakane, Ryo Mizunuma, Keita Matsuoka, Yasumasa Joti, Kensuke Tono, Eriko Nango, So Iwata, Toru Nakatsu, and Hiroaki Kato
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Science ,sample delivery ,Cyanidioschyzon merolae ,General Chemistry ,Condensed Matter Physics ,Biochemistry ,Research Papers ,XFELs ,ABC transporters ,LCP ,protein structures ,multi-drug exporters ,SFX ,CmABCB1 ,General Materials Science ,serial crystallography ,lipidic mesophase - Abstract
The 2.22 Å crystal structure of a multi-drug exporter, CmABCB1, was determined by the LCP-SFX method using the XFEL beamline at SACLA. The lipid bilayer-embedded structure revealed new insights about the substrate transport mechanism of CmABCB1., CmABCB1 is a Cyanidioschyzon merolae homolog of human ABCB1, a well known ATP-binding cassette (ABC) transporter responsible for multi-drug resistance in various cancers. Three-dimensional structures of ABCB1 homologs have revealed the snapshots of inward- and outward-facing states of the transporters in action. However, sufficient information to establish the sequential movements of the open–close cycles of the alternating-access model is still lacking. Serial femtosecond crystallography (SFX) using X-ray free-electron lasers has proven its worth in determining novel structures and recording sequential conformational changes of proteins at room temperature, especially for medically important membrane proteins, but it has never been applied to ABC transporters. In this study, 7.7 monoacylglycerol with cholesterol as the host lipid was used and obtained well diffracting microcrystals of the 130 kDa CmABCB1 dimer. Successful SFX experiments were performed by adjusting the viscosity of the crystal suspension of the sponge phase with hydroxypropyl methylcellulose and using the high-viscosity sample injector for data collection at the SACLA beamline. An outward-facing structure of CmABCB1 at a maximum resolution of 2.22 Å is reported, determined by SFX experiments with crystals formed in the lipidic cubic phase (LCP-SFX), which has never been applied to ABC transporters. In the type I crystal, CmABCB1 dimers interact with adjacent molecules via not only the nucleotide-binding domains but also the transmembrane domains (TMDs); such an interaction was not observed in the previous type II crystal. Although most parts of the structure are similar to those in the previous type II structure, the substrate-exit region of the TMD adopts a different configuration in the type I structure. This difference between the two types of structures reflects the flexibility of the substrate-exit region of CmABCB1, which might be essential for the smooth release of various substrates from the transporter.
- Published
- 2022
172. Deciphering the RRM-RNA recognition code: A computational analysis
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Roca-Martínez, Joel, Dhondge, Hrishikesh, Sattler, Michael, Vranken, Wim F., Faculty of Sciences and Bioengineering Sciences, Department of Bio-engineering Sciences, Structural Biology Brussels, Artificial Intelligence, Informatics and Applied Informatics, Chemistry, and Basic (bio-) Medical Sciences
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RRM ,Cellular and Molecular Neuroscience ,Protein alignment ,Computational Theory and Mathematics ,Ecology ,Modeling and Simulation ,protein structures ,Genetics ,RNA binding ,Prediction ,Molecular Biology ,Ecology, Evolution, Behavior and Systematics ,Predictor - Abstract
RNA recognition motifs (RRM) are the most prevalent class of RNA binding domains in eucaryotes. Their RNA binding preferences have been investigated for almost two decades, and even though some RRM domains are now very well described, their RNA recognition code has remained elusive. An increasing number of experimental structures of RRM-RNA complexes has become available in recent years. Here, we perform an in-depth computational analysis to derive an RNA recognition code for canonical RRMs. We present and validate a computational scoring method to estimate the binding between an RRM and a single stranded RNA, based on structural data from a carefully curated multiple sequence alignment, which can predict RRM binding RNA sequence motifs based on the RRM protein sequence. Given the importance and prevalence of RRMs in humans and other species, this tool could help design RNA binding motifs with uses in medical or synthetic biology applications, leading towards the de novo design of RRMs with specific RNA recognition.
- Published
- 2023
173. Structures along reaction pathways optimized in QM/MM calculations for modeling of flavin functionalization in the RutA monooxygenase
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Nemukhin Alexander, Grigorenko Bella, and Domratcheva Tatiana
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protein structures ,dioxygen ,flavins ,atomic coordinates - Abstract
Files with the atomic coordinates (pdb-format) of the structures optimized in QM/MM calculations for the project "QM/MM modeling of flavin functionalization in the RutA monooxygenase"
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- 2023
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174. findMySequence: a neural-network-based approach for identification of unknown proteins in X-ray crystallography and cryo-EM
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Grzegorz Chojnowski, Adam J. Simpkin, Diego A. Leonardo, Wolfram Seifert-Davila, Dan E. Vivas-Ruiz, Ronan M. Keegan, and Daniel J. Rigden
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Crystallography ,General Chemistry ,bioinformatics ,Condensed Matter Physics ,neural networks ,Biochemistry ,Research Papers ,structure determination ,QD901-999 ,SIMBAD ,protein structures ,cryo-EM ,General Materials Science ,protein sequences ,REDES NEURAIS ,findMySequence - Abstract
findMySequence is presented – a machine-learning method for the identification of unknown proteins and sequence-assignment validation in cryo-EM and X-ray crystallography., Although experimental protein-structure determination usually targets known proteins, chains of unknown sequence are often encountered. They can be purified from natural sources, appear as an unexpected fragment of a well characterized protein or appear as a contaminant. Regardless of the source of the problem, the unknown protein always requires characterization. Here, an automated pipeline is presented for the identification of protein sequences from cryo-EM reconstructions and crystallographic data. The method’s application to characterize the crystal structure of an unknown protein purified from a snake venom is presented. It is also shown that the approach can be successfully applied to the identification of protein sequences and validation of sequence assignments in cryo-EM protein structures.
- Published
- 2021
175. Progress in Developing Inhibitors of SARS-CoV-2 3C-Like Protease
- Author
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Qingxin Li and CongBao Kang
- Subjects
COVID-19 ,SARS-CoV-2 ,drug discovery ,protease inhibitor ,protein structures ,antivirals ,Biology (General) ,QH301-705.5 - Abstract
Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The viral outbreak started in late 2019 and rapidly became a serious health threat to the global population. COVID-19 was declared a pandemic by the World Health Organization in March 2020. Several therapeutic options have been adopted to prevent the spread of the virus. Although vaccines have been developed, antivirals are still needed to combat the infection of this virus. SARS-CoV-2 is an enveloped virus, and its genome encodes polyproteins that can be processed into structural and nonstructural proteins. Maturation of viral proteins requires cleavages by proteases. Therefore, the main protease (3 chymotrypsin-like protease (3CLpro) or Mpro) encoded by the viral genome is an attractive drug target because it plays an important role in cleaving viral polyproteins into functional proteins. Inhibiting this enzyme is an efficient strategy to block viral replication. Structural studies provide valuable insight into the function of this protease and structural basis for rational inhibitor design. In this review, we describe structural studies on the main protease of SARS-CoV-2. The strategies applied in developing inhibitors of the main protease of SARS-CoV-2 and currently available protein inhibitors are summarized. Due to the availability of high-resolution structures, structure-guided drug design will play an important role in developing antivirals. The availability of high-resolution structures, potent peptidic inhibitors, and diverse compound scaffolds indicate the feasibility of developing potent protease inhibitors as antivirals for COVID-19.
- Published
- 2020
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176. Analysis of Protein Disorder Predictions in the Light of a Protein Structural Alphabet
- Author
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Alexandre G. de Brevern
- Subjects
protein structures ,intrinsic disorder proteins ,intrinsic disorder regions ,X-ray structures ,nuclear magnetic resonance ,molecular dynamics ,Microbiology ,QR1-502 - Abstract
Intrinsically-disordered protein (IDP) characterization was an amazing change of paradigm in our classical sequence-structure-function theory. Moreover, IDPs are over-represented in major disease pathways and are now often targeted using small molecules for therapeutic purposes. This has had created a complex continuum from order-that encompasses rigid and flexible regions-to disorder regions; the latter being not accessible through classical crystallographic methodologies. In X-ray structures, the notion of order is dictated by access to resolved atom positions, providing rigidity and flexibility information with low and high experimental B-factors, while disorder is associated with the missing (non-resolved) residues. Nonetheless, some rigid regions can be found in disorder regions. Using ensembles of IDPs, their local conformations were analyzed in the light of a structural alphabet. An entropy index derived from this structural alphabet allowed us to propose a continuum of states from rigidity to flexibility and finally disorder. In this study, the analysis was extended to comparing these results to disorder predictions, underlying a limited correlation, and so opening new ideas to characterize and predict disorder.
- Published
- 2020
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177. A Practical Perspective on the Roles of Solution NMR Spectroscopy in Drug Discovery
- Author
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Qingxin Li and CongBao Kang
- Subjects
NMR ,drug discovery ,protein structures ,protein dynamics ,fragment-based drug design ,fragment screening ,Organic chemistry ,QD241-441 - Abstract
Solution nuclear magnetic resonance (NMR) spectroscopy is a powerful tool to study structures and dynamics of biomolecules under physiological conditions. As there are numerous NMR-derived methods applicable to probe protein–ligand interactions, NMR has been widely utilized in drug discovery, especially in such steps as hit identification and lead optimization. NMR is frequently used to locate ligand-binding sites on a target protein and to determine ligand binding modes. NMR spectroscopy is also a unique tool in fragment-based drug design (FBDD), as it is able to investigate target-ligand interactions with diverse binding affinities. NMR spectroscopy is able to identify fragments that bind weakly to a target, making it valuable for identifying hits targeting undruggable sites. In this review, we summarize the roles of solution NMR spectroscopy in drug discovery. We describe some methods that are used in identifying fragments, understanding the mechanism of action for a ligand, and monitoring the conformational changes of a target induced by ligand binding. A number of studies have proven that 19F-NMR is very powerful in screening fragments and detecting protein conformational changes. In-cell NMR will also play important roles in drug discovery by elucidating protein-ligand interactions in living cells.
- Published
- 2020
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178. Protein Binding Interfaces and Their Binding Hot Spot Prediction: A Survey
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Liu, Qian, Li, Jinyan, Wang, Xiangdong, Series editor, and Shen, Bairong, editor
- Published
- 2013
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179. Protein Data Bank Japan: Celebrating our 20th anniversary during a global pandemic as the Asian hub of three dimensional macromolecular structural data
- Author
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Gert-Jan Bekker, Takahiro Kudou, Yasuyo Ikegawa, Takeshi Kawabata, Masashi Yokochi, Genji Kurisu, Hirofumi Suzuki, Kei Yura, Toshimichi Fujiwara, and Takeshi Iwata
- Subjects
Models, Molecular ,PDB ,Open science ,Protein Conformation ,Computer science ,Protein Data Bank (RCSB PDB) ,Biochemistry ,World Wide Web ,User-Computer Interface ,Viral Proteins ,Japan ,COVID‐19 ,Pandemic ,Animals ,Humans ,Databases, Protein ,EMDB ,Molecular Biology ,Structure (mathematical logic) ,Tools for Protein Science ,SARS-CoV-2 ,COVID-19 ,Proteins ,computer.file_format ,Protein Data Bank ,Visualization ,Outreach ,Anniversaries and Special Events ,BMRB ,protein structures ,User interface ,computer ,Software - Abstract
Protein Data Bank Japan (PDBj), a founding member of the worldwide Protein Data Bank (wwPDB) has accepted, processed and distributed experimentally determined biological macromolecular structures for 20 years. During that time, we have continuously made major improvements to our query search interface of PDBj Mine 2, the BMRBj web interface, and EM Navigator for PDB/BMRB/EMDB entries. PDBj also serves PDB‐related secondary database data, original web‐based modeling services such as Homology modeling of complex structure (HOMCOS), visualization services and utility tools, which we have continuously enhanced and expanded throughout the years. In addition, we have recently developed several unique archives, BSM‐Arc for computational structure models, and XRDa for raw X‐ray diffraction images, both of which promote open science in the structural biology community. During the COVID‐19 pandemic, PDBj has also started to provide feature pages for COVID‐19 related entries across all available archives at PDBj from raw experimental data and PDB structural data to computationally predicted models, while also providing COVID‐19 outreach content for high school students and teachers.
- Published
- 2021
180. Challenges in bridging the gap between protein structure prediction and functional interpretation.
- Author
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Varadi M, Tsenkov M, and Velankar S
- Abstract
The rapid evolution of protein structure prediction tools has significantly broadened access to protein structural data. Although predicted structure models have the potential to accelerate and impact fundamental and translational research significantly, it is essential to note that they are not validated and cannot be considered the ground truth. Thus, challenges persist, particularly in capturing protein dynamics, predicting multi-chain structures, interpreting protein function, and assessing model quality. Interdisciplinary collaborations are crucial to overcoming these obstacles. Databases like the AlphaFold Protein Structure Database, the ESM Metagenomic Atlas, and initiatives like the 3D-Beacons Network provide FAIR access to these data, enabling their interpretation and application across a broader scientific community. Whilst substantial advancements have been made in protein structure prediction, further progress is required to address the remaining challenges. Developing training materials, nurturing collaborations, and ensuring open data sharing will be paramount in this pursuit. The continued evolution of these tools and methodologies will deepen our understanding of protein function and accelerate disease pathogenesis and drug development discoveries., (© 2023 The Authors. Proteins: Structure, Function, and Bioinformatics published by Wiley Periodicals LLC.)
- Published
- 2023
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181. Titin UN2A Acts as a Stable, Non-Polymorphic Scaffold in its Binding to CARP.
- Author
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Stehle J, Fleming JR, Bauer PM, Mayans O, and Drescher M
- Abstract
The N2A segment of titin functions as a pivotal hub for signal transduction and interacts with various proteins involved in structural support, chaperone activities, and transcriptional regulation. Notably, the "unique N2A" (UN2A) subdomain has been shown to interact with the stress-regulated cardiac ankyrin repeat protein (CARP), which contributes to the regulation of sarcomeric stiffness. Previously, the UN2A domain's three-dimensional structure was modelled based on its secondary structure content identified by NMR spectroscopy, considering the domain in isolation. In this study, we report experimental long-range distance distributions by electron paramagnetic resonance (EPR) spectroscopy between the three helixes within the UN2A domain linked to the immunoglobulin domain I81 in the presence and absence of CARP. The data confirm the central three-helix bundle fold of UN2A and show that this adopts a compact and stable conformation in absence of CARP. After binding to CARP, no significant conformational change was observed, suggesting that the UN2A domain retains its structure upon binding to CARP thereby, mediating the interaction approximately as a rigid-body., (© 2023 The Authors. ChemBioChem published by Wiley-VCH GmbH.)
- Published
- 2023
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182. New insights into comprehensive analysis of magnesium transporter ( MGT ) gene family in rice ( Oryza sativa L.).
- Author
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Mohamadi SF, Babaeian Jelodar N, Bagheri N, Nematzadeh G, and Hashemipetroudi SH
- Abstract
Magnesium transporters (MGTs) regulate magnesium absorption, transport, and redistribution in higher plants. To investigate the role of the Oryza sativa MGTs gene family members under salt stress, this study analyzed the protein properties, gene structure, phylogenetic relationship, synteny patterns, expression, and co-expression networks of 23 non-redundant OsMGT . The evolutionary relationship of the OsMGT gene family was fully consistent with their functional domain, and were divided into three main classes based on the conserved domain: MMgT, CorA-like, and NIPA. The α/β patterns in the protein structures were highly similar in the CorA-like and NIPA members, with the conserved structures in the Mg
2+ -binding and catalytic regions. The CorA-like clade-related proteins demonstrated the highest numbers of protein channels with Pro, Ser, Lys, Gly, and Tyr, as the critical binding residues. The expression analysis of OsMGT genes in various tissues showed that MGTs ' gene family may possess critical functions during rice development. Gene expression analysis of candidate OsMGT using reverse-transcription quantitative real-time PCR (RT-qPCR) found that four OsMGT genes exhibited different expression patterns in salt-sensitive and salt-tolerant rice genotypes. We hypothesize that the OsMGT gene family members may be involved in responses to salt stress. These findings could be useful for further functional investigation of MGTs as well as defining their involvement in abiotic stress studies., Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-023-03735-4., Competing Interests: Conflict of interestThe authors declare no conflict of interest, financial, or otherwise., (© King Abdulaziz City for Science and Technology 2023. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)- Published
- 2023
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183. Integrated Analysis of Cross-Links and Dead-End Peptides for Enhanced Interpretation of Quantitative XL-MS.
- Author
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Keller A, Tang X, and Bruce JE
- Subjects
- Animals, Mice, Mass Spectrometry methods, Protein Conformation, Solvents, Cross-Linking Reagents chemistry, Peptides analysis, Proteins analysis
- Abstract
Chemical cross-linking with mass spectrometry provides low-resolution structural information on proteins in cells and tissues. Combined with quantitation, it can identify changes in the interactome between samples, for example, control and drug-treated cells or young and old mice. A difference can originate from protein conformational changes that alter the solvent-accessible distance separating the cross-linked residues. Alternatively, a difference can result from conformational changes localized to the cross-linked residues, for example, altering the solvent exposure or reactivity of those residues or post-translational modifications of the cross-linked peptides. In this manner, cross-linking is sensitive to a variety of protein conformational features. Dead-end peptides are cross-links attached only at one end to a protein with the other terminus being hydrolyzed. As a result, changes in their abundance reflect only conformational changes localized to the attached residue. For this reason, analyzing both quantified cross-links and their corresponding dead-end peptides can help elucidate the likely conformational changes giving rise to observed differences in cross-link abundance. We describe analysis of dead-end peptides in the XLinkDB public cross-link database and, with quantified mitochondrial data isolated from failing heart versus healthy mice, show how a comparison of abundance ratios between cross-links and their corresponding dead-end peptides can be leveraged to reveal possible conformational explanations.
- Published
- 2023
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184. Decoding Protein Dynamics in Cells Using Chemical Cross-Linking and Hierarchical Analysis.
- Author
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Zhang B, Gong Z, Zhao L, An Y, Gao H, Chen J, Liang Z, Liu M, Zhang Y, Zhao Q, and Zhang L
- Subjects
- Mass Spectrometry, Protein Conformation, Molecular Dynamics Simulation, Intrinsically Disordered Proteins chemistry
- Abstract
Protein dynamics play a crucial role in their diverse functions. The intracellular environment significantly influences protein dynamics, particularly for intrinsically disordered proteins (IDPs). To comprehensively capture structural information from various proteins within cells and characterize protein dynamics, chemical cross-linking mass spectrometry was employed. In this study, we introduce a hierarchical decoding strategy that enables the investigation of protein dynamics in vivo. Computational analysis based on distance restraints derived from cross-links is used to infer protein dynamics in cells. To facilitate this analysis, we leverage the prior structure obtained from AlphaFold2. By employing this strategy, we can characterize the full-length structure of multi-domain proteins taking into account their distinct dynamic features. Furthermore, by combining restraint sampling with an unbiased sampling and evaluation approach, we can provide a comprehensive description of the intrinsic motion of IDPs. Consequently, the hierarchical strategy we propose holds significant potential in advancing our understanding of the molecular mechanisms that undelie protein functions in cells., (© 2023 Wiley-VCH GmbH.)
- Published
- 2023
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185. Structural Space of the Duffy Antigen/Receptor for Chemokines' Intrinsically Disordered Ectodomain 1 Explored by Temperature Replica-Exchange Molecular Dynamics Simulations.
- Author
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Kranjc A, Narwani TJ, Abby SS, and de Brevern AG
- Subjects
- Humans, Chemokines, Receptors, Antigen, Temperature, Malaria, Vivax, Molecular Dynamics Simulation
- Abstract
Plasmodium vivax malaria affects 14 million people each year. Its invasion requires interactions between the parasitic Duffy-binding protein ( Pv DBP) and the N-terminal extracellular domain (ECD1) of the host's Duffy antigen/receptor for chemokines (DARC). ECD1 is highly flexible and intrinsically disordered, therefore it can adopt different conformations. We computationally modeled the challenging ECD1 local structure. With T-REMD simulations, we sampled its dynamic behavior and collected its most representative conformations. Our results suggest that most of the DARC ECD1 domain remains in a disordered state during the simulated time. Globular local conformations are found in the analyzed local free-energy minima. These globular conformations share an α-helix spanning residues Ser18 to Ser29 and in many cases they comprise an antiparallel β-sheet, whose β-strands are formed around residues Leu10 and Ala49. The formation of a parallel β-sheet is almost negligible. So far, progress in understanding the mechanisms forming the basis of the P. vivax malaria infection of reticulocytes has been hampered by experimental difficulties, along with a lack of DARC structural information. Our collection of the most probable ECD1 structural conformations will help to advance modeling of the DARC structure and to explore DARC-ECD1 interactions with a range of physiological and pathological ligands.
- Published
- 2023
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186. Structure-Informed Protein Language Models are Robust Predictors for Variant Effects.
- Author
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Sun Y and Shen Y
- Abstract
Predicting protein variant effects through machine learning is often challenged by the scarcity of experimentally measured effect labels. Recently, protein language models (pLMs) emerge as zero-shot predictors without the need of effect labels, by modeling the evolutionary distribution of functional protein sequences. However, biological contexts important to variant effects are implicitly modeled and effectively marginalized. By assessing the sequence awareness and the structure awareness of pLMs, we find that their improvements often correlate with better variant effect prediction but their tradeoff can present a barrier as observed in over-finetuning to specific family sequences. We introduce a framework of structure-informed pLMs (SI-pLMs) to inject protein structural contexts purposely and controllably, by extending masked sequence denoising in conventional pLMs to cross-modality denoising. Our SI-pLMs are applicable to revising any sequence-only pLMs through model architecture and training objectives. They do not require structure data as model inputs for variant effect prediction and only use structures as context provider and model regularizer during training. Numerical results over deep mutagenesis scanning benchmarks show that our SI-pLMs, despite relatively compact sizes, are robustly top performers against competing methods including other pLMs, regardless of the target protein family's evolutionary information content or the tendency to overfitting / over-finetuning. Learned distributions in structural contexts could enhance sequence distributions in predicting variant effects. Ablation studies reveal major contributing factors and analyses of sequence embeddings provide further insights. The data and scripts are available at https://github.com/Stephen2526/Structure-informed_PLM.git., Competing Interests: Additional Declarations: No competing interests reported.
- Published
- 2023
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187. Interface Interactions of the Bowman–Birk Inhibitor BTCI in a Ternary Complex with Trypsin and Chymotrypsin Evaluated by Semiempirical Quantum Mechanical Calculations.
- Author
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Honda, Diego Elias, Martins, João Batista Lopes, Ventura, Manuel Mateus, Eyrilmez, Saltuk Mustafa, Lepšík, Martin, Hobza, Pavel, Pecina, Adam, and Freitas, Sonia Maria
- Subjects
- *
BOWMAN-Birk inhibitor , *COMPLEX compounds , *CHYMOTRYPSIN , *QUANTUM mechanics , *PROTEASE inhibitors , *PROTEASOMES - Abstract
Black‐eyed pea trypsin and chymotrypsin inhibitor (BTCI) is a small protein from Bowman–Birk protease inhibitor family, which simultaneously inhibits trypsin and chymotrypsin. Through the inhibition of trypsin‐ and chymotrypsin‐like sites on the 20S subunit of human proteasome, BTCI acts as a potent anticarcinogenic agent inducing apoptosis in breast cancer cells. Because of the lack of crystallographic information of the BTCI‐proteasome complex, we analyze here the BTCI‐chymotrypsin and BTCI‐trypsin interfaces using computations. We adopt the corrected semiempirical quantum‐mechanical methods in combination with implicit description of the water environment. Firstly, we carefully check the representativeness of smaller systems by fragmentation and analyzing the convergence of the overall interaction energies. Then, we use the "virtual glycine scan" technique to understand the binary complex formation, identifying the most contributing amino acid side chains in the interfaces. Besides detailed quantification of all important residue contributions, the importance of Lys26 and Phe53 in the BTCI and Asp186 (trypsin) and Ser195 (chymotrypsin) residues is confirmed. In summary, we have worked out an accurate and efficient in silico protocol for protein–protein interfaces, which can be later used for studying the inhibition of 20S proteasome. We describe the interfaces of the Bowman–Birk inhibitor (BTCI) with proteases trypsin and chymotrypsin by semiempirical quantum‐mechanical methods and give an implicit description of the water environment. The importance of amino acids at the interfaces, for example Lys26 and Phe53 in the BTCI and Asp186 (trypsin) and Ser195 (chymotrypsin), was identified and the side‐chain contributions were quantified. [ABSTRACT FROM AUTHOR]
- Published
- 2018
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- View/download PDF
188. Stabilization of Mineral Precursors by Intrinsically Disordered Proteins.
- Author
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Rao, Ashit, Drechsler, Markus, Schiller, Stefan, Scheffner, Martin, Gebauer, Denis, and Cölfen, Helmut
- Subjects
- *
CHEMICAL precursors , *PROTEIN structure , *BIOMATERIALS , *NUCLEATION , *CRYSTALLIZATION - Abstract
Abstract: Biogenic nucleation and crystallization occur in confined spaces with defined interfacial properties. However, the regulatory functions of organic players in the stabilization and transport of inorganic precursors such as ion clusters, liquid‐condensed phases, and amorphous particles are unclear. Given the prevalence of unstructured proteins in biogenic materials, the present study investigates the effects of biomineral‐associated, intrinsically disordered protein domains with simple and repetitive amino acid compositions on mineral nucleation and their capability to form distinct supramolecular assemblies. The quantitative assessment and structural evaluation of the nucleation process reveal that disordered regions confine hydrated mineral precursors within vesicles, transiently suppressing mineral precipitation. Stabilization of the amorphous mineral is attributed to protein self‐association and restructuration toward β‐configurations, triggered by specific bioinorganic interactions. In consequence, the conditioned macromolecules localize at phase boundaries formed upon liquid–liquid demixing of mineral precursors and stabilize the fluidic mineral precursors against crystallization. Thus, the conformational plasticity and self‐association of intrinsically disordered sequences in response to crystallization environments mediates the selection of functional macromolecular subensembles dedicated to biomaterial growth. [ABSTRACT FROM AUTHOR]
- Published
- 2018
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- View/download PDF
189. On the Development of Electron Cryo‐Microscopy (Nobel Lecture).
- Author
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Dubochet, Jacques
- Subjects
- *
ELECTRON microscopy , *CRYOMICROSCOPY , *BACTERIOPHAGES , *PROTEIN structure - Published
- 2018
- Full Text
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190. Similarity/dissimilarity analysis of protein structures based on Markov random fields.
- Author
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Wu, Jiaqi, Zhou, Tao, Tao, Jin, Hai, Yabing, Ye, Fei, Liu, Xiaoqing, and Dai, Qi
- Subjects
- *
PROTEIN structure , *MARKOV random fields , *CYCLIC peptides , *ORGANIC cyclic compounds , *PROTEIN analysis - Abstract
Protein Structure Similarity plays an important role in study on functional properties of proteins and evolutionary study. Many efficient methods have been proposed to advance protein structural comparison, but there are still some challenges in the contact strength definitions and similarity measures. In this work, we schemed out a new method to analyze the similarity/dissimilarity of the protein structures based on Markov random fields. We evaluated the proposed method with two experiments and compared it with the competing methods The results indicate that the proposed method exhibits a strong ability to detect the similarities/dissimilarities among the conformation of different cyclic peptides and protein structures. We also found that the alpha-C, oxygen O and N allow us to extract more conserved structures of the proteins, and Markov random fields with 2-point cliques (V) and orders 3 and 1 are more efficient in detecting the similarities/dissimilarities among different protein structures. This understanding can be used to design more powerful methods for similarities/dissimilarities analysis of different protein structures. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
- View/download PDF
191. Isonitrile Formation by a Non‐Heme Iron(II)‐Dependent Oxidase/Decarboxylase.
- Author
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Harris, Nicholas C., Born, David A., Cai, Wenlong, Huang, Yaobing, Martin, Joelle, Khalaf, Ryan, Drennan, Catherine L., and Zhang, Wenjun
- Subjects
- *
ISOCYANIDES , *OXIDASES , *IRON , *DECARBOXYLASES , *BIOSYNTHESIS , *NATURAL products - Abstract
Abstract: The electron‐rich isonitrile is an important functionality in bioactive natural products, but its biosynthesis has been restricted to the IsnA family of isonitrile synthases. We herein provide the first structural and biochemical evidence of an alternative mechanism for isonitrile formation. ScoE, a putative non‐heme iron(II)‐dependent enzyme from Streptomyces coeruleorubidus, was shown to catalyze the conversion of (R)‐3‐((carboxymethyl)amino)butanoic acid to (R)‐3‐isocyanobutanoic acid through an oxidative decarboxylation mechanism. This work further provides a revised scheme for the biosynthesis of a unique class of isonitrile lipopeptides, of which several members are critical for the virulence of pathogenic mycobacteria. [ABSTRACT FROM AUTHOR]
- Published
- 2018
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- View/download PDF
192. In Situ Study of the Function of Bacterioruberin in the Dual‐Chromophore Photoreceptor Archaerhodopsin‐4.
- Author
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Sun, Chao, Ding, Xiaoyan, Cui, Haolin, Yang, Yanan, Chen, Sijin, Watts, Anthony, and Zhao, Xin
- Subjects
- *
CHROMOPHORES , *ION pumps , *THERMODYNAMIC equilibrium , *NUCLEAR magnetic resonance , *MOLECULAR spectroscopy - Abstract
Abstract: While certain archaeal ion pumps have been shown to contain two chromophores, retinal and the carotenoid bacterioruberin, the functions of bacterioruberin have not been well explored. To address this research gap, recombinant archaerhodopsin‐4 (aR4), either with retinal only or with both retinal and bacterioruberin chromophores, was successfully expressed together with endogenous lipids in H. salinarum L33 and MPK409 respectively. In situ solid‐state NMR, supported by molecular spectroscopy and functional assays, revealed for the first time that the retinal thermal equilibrium in the dark‐adapted state is modulated by bacterioruberin binding through a cluster of aromatic residues on helix E. Bacterioruberin not only stabilizes the protein trimeric structure but also affects the photocycle kinetics and the ATP formation rate. These new insights may be generalized to other receptors and proteins in which metastable thermal equilibria and functions are perturbed by ligand binding. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
- View/download PDF
193. An Engineered Lithocholate‐Based Facial Amphiphile Stabilizes Membrane Proteins: Assessing the Impact of Detergent Customizability on Protein Stability.
- Author
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Das, Manabendra, Du, Yang, Mortensen, Jonas S., Bae, Hyoung Eun, Byrne, Bernadette, Loland, Claus J., Kobilka, Brian K., and Chae, Pil Seok
- Subjects
- *
LITHOCHOLIC acid , *AMPHIPHILES , *MEMBRANE proteins , *PROTEIN stability , *MICELLES - Abstract
Abstract: Amphiphiles are critical tools for the structural and functional study of membrane proteins. Membrane proteins encapsulated by conventional head‐to‐tail detergents tend to undergo structural degradation, necessitating the development of structurally novel agents with improved efficacy. In recent years, facial amphiphiles have yielded encouraging results in terms of membrane protein stability. Herein, we report a new facial detergent (i.e., LFA‐C4) that confers greater stability to tested membrane proteins than the bola form analogue. Owing to the increased facial property and the adaptability of the detergent micelles in complex with different membrane proteins, LFA‐C4 yields increased stability compared to n‐dodecyl‐β‐ d‐maltoside (DDM). Thus, this study not only describes a novel maltoside detergent with enhanced protein‐stabilizing properties, but also shows that the customizable nature of a detergent plays an important role in the stabilization of membrane proteins. Owing to both synthetic convenience and enhanced stabilization efficacy for a range of membrane proteins, the new agent has major potential in membrane protein research. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
- View/download PDF
194. Molecular Insight into the Mg2+‐Dependent Allosteric Control of Indole Prenylation by Aromatic Prenyltransferase AmbP1.
- Author
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Awakawa, Takayoshi, Mori, Takahiro, Nakashima, Yu, Zhai, Rui, Wong, Chin Piow, Hillwig, Matthew L., Liu, Xinyu, and Abe, Ikuro
- Subjects
- *
MAGNESIUM ions , *ALLOSTERIC regulation , *ISOPRENYLATION , *DIMETHYLALLYLTRANSTRANSFERASE , *BINDING sites - Abstract
Abstract: AmbP1 is a cyanobacterial aromatic prenyltransferase and a dedicated synthase for (R)‐3‐geranyl‐3‐isocyanovinyl indolenine (2), the biogenetic precursor for hapalindole‐type alkaloids. The regioselective geranylation of cis‐indolyl vinyl isonitrile (1) by the standalone AmbP1 to give 2 has been shown to require a magnesium ion (Mg2+) to suppress the formation of cis‐2‐geranylindolyl vinyl isonitrile (3). Here, we report high‐resolution crystal structures of AmbP1 in complex with 1 and geranyl S‐thiodiphosphate (GSPP) in the presence and absence of a Mg2+ effector. The comparative study of these structures revealed a unique allosteric binding site for Mg2+ that modulates the conformation of 1 in the active site of AmbP1 for its selective geranylation. This work defines the structural basis for AmbP1 catalysis in the biogenesis of hapalindole‐type alkaloids and provides the first atomic‐level insight to the allosteric regulation of prenyltransferases. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
- View/download PDF
195. Cross-Linking/Mass Spectrometry for Studying Protein Structures and Protein-Protein Interactions: Where Are We Now and Where Should We Go from Here?
- Author
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Sinz, Andrea
- Subjects
- *
PROTEIN structure , *PROTEIN crosslinking , *PROTEIN-protein interactions , *NUCLEAR magnetic resonance spectroscopy , *X-ray crystallography - Abstract
Structural mass spectrometry (MS) is gaining increasing importance for deriving valuable three-dimensional structural information on proteins and protein complexes, and it complements existing techniques, such as NMR spectroscopy and X-ray crystallography. Structural MS unites different MS-based techniques, such as hydrogen/deuterium exchange, native MS, ion-mobility MS, protein footprinting, and chemical cross-linking/MS, and it allows fundamental questions in structural biology to be addressed. In this Minireview, I will focus on the cross-linking/MS strategy. This method not only delivers tertiary structural information on proteins, but is also increasingly being used to decipher protein interaction networks, both in vitro and in vivo. Cross-linking/MS is currently one of the most promising MS-based approaches to derive structural information on very large and transient protein assemblies and intrinsically disordered proteins. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
- View/download PDF
196. Two Histidines in an α‐Helix: A Rigid Co2+‐Binding Motif for PCS Measurements by NMR Spectroscopy.
- Author
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Bahramzadeh, Alireza, Jiang, Hailun, Huber, Thomas, and Otting, Gottfried
- Subjects
- *
CARBON monoxide , *METAL ions , *HISTIDINE , *NUCLEAR magnetic resonance spectroscopy , *ENCAPSULATION (Catalysis) - Abstract
Abstract: Pseudocontact shifts (PCS) generated by paramagnetic metal ions present valuable long‐range information in the study of protein structural biology by nuclear magnetic resonance (NMR) spectroscopy. Faithful interpretation of PCSs, however, requires complete immobilization of the metal ion relative to the protein, which is difficult to achieve with synthetic metal tags. We show that two histidine residues in sequential turns of an α‐helix provide a binding site for a Co2+ ion, which positions the metal ion in a uniquely well‐defined and predictable location. Exchange between the bound and free cobalt is slow on the timescale defined by chemical shifts, but the NMR resonance assignments are nonetheless readily transferred from the diamagnetic to the paramagnetic NMR spectrum by an IzSz‐exchange experiment. The double‐histidine‐Co2+ motif offers a straightforward, inexpensive, and convenient way of generating precision PCSs in proteins. [ABSTRACT FROM AUTHOR]
- Published
- 2018
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- View/download PDF
197. Common Patterns in Chaperone Interactions with a Native Client Protein.
- Author
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He, Lichun and Hiller, Sebastian
- Subjects
- *
MOLECULAR chaperones , *PROTEIN analysis , *SURFACE chemistry , *CRYSTAL structure , *MOLECULAR recognition - Abstract
Abstract: Many molecular chaperones are promiscuous and interact with a wide range of unfolded, quasi‐native, and native client proteins. The mechanisms by which chaperones interact with the highly diverse structures of native clients thus remain puzzling. In this work, we investigate at the atomic level how three ATP‐independent chaperones interact with a β‐sheet‐rich protein, the Fyn SH3 domain. The results reveal that the chaperone Spy recognizes the locally frustrated surface of the client Fyn SH3 and that the interaction is transient and highly dynamic, leaving the chaperone‐interacting surface on Fyn SH3 solvent accessible. The two alternative molecular chaperones SurA and Skp recognize the same locally frustrated surface of the Fyn SH3 domain. These results indicate dynamic recognition of frustrated segments as a common mechanism underlying the chaperone–native client interaction, which also provides a basis for chaperone promiscuousness. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
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198. Immune Checkpoint PD-1/PD-L1: Is There Life Beyond Antibodies?
- Author
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Konstantinidou, Markella, Zarganes‐Tzitzikas, Tryfon, Magiera‐Mularz, Katarzyna, Holak, Tad A., and Dömling, Alexander
- Subjects
- *
CANCER immunotherapy , *MONOCLONAL antibodies , *PROGRAMMED cell death 1 receptors , *T cell receptors ,IMMUNE system physiology - Abstract
The PD-1/PD-L1 interaction has emerged as a significant target in cancer immunotherapy. Current medications include monoclonal antibodies, which have shown impressive clinical results in the treatment of several types of tumors. The cocrystal structure of human PD- 1 and PD-L1 is expected to be a valuable starting point for the design of novel inhibitors, along with the recent crystal structures with monoclonal antibodies, small molecules, and macrocycles. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
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199. Roles of Amphipathicity and Hydrophobicity in the Micelle‐Driven Structural Switch of a 14‐mer Peptide Core from a Choline‐Binding Repeat.
- Author
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Zamora‐Carreras, Héctor, Maestro, Beatriz, Strandberg, Erik, Ulrich, Anne S., Sanz, Jesús M., and Jiménez, M. Ángeles
- Subjects
- *
PEPTIDE analysis , *CHOLINE , *STRUCTURAL analysis (Science) , *AUTOLYSINS , *HYDROPHOBIC interactions , *CIRCULAR dichroism - Abstract
Abstract: Choline‐binding repeats (CBRs) are ubiquitous sequences with a β‐hairpin core that are found in the surface proteins of several microorganisms such as
S. pneumoniae (pneumococcus). Previous studies on a 14‐mer CBR sequence derived from the pneumoccal LytA autolysin (LytA239–252 peptide) have demonstrated a switch behaviour for this peptide, so that it acquires a stable, native‐like β‐hairpin conformation in aqueous solution but is reversibly transformed into an amphipathic α‐helix in the presence of detergent micelles. With the aim of understanding the factors responsible for this unusual β‐hairpin to α‐helix transition, and to specifically assess the role of peptide hydrophobicity and helical amphipathicity in the process, we designed a series of LytA239–252 variants affecting these two parameters and studied their interaction with dodecylphosphocholine (DPC) micelles by solution NMR, circular dichroism and fluorescence spectroscopies. Our results indicate that stabilising cross‐strand interactions become essential for β‐hairpin stability in the absence of optimal turn sequences. Moreover, both amphipathicity and hydrophobicity display comparable importance for helix stabilisation of CBR‐derived peptides in micelles, indicating that these sequences represent a novel class of micelle/membrane‐interacting peptides. [ABSTRACT FROM AUTHOR]- Published
- 2018
- Full Text
- View/download PDF
200. Construction of a Triangle‐Shaped Trimer and a Tetrahedron Using an α‐Helix‐Inserted Circular Permutant of Cytochrome <italic>c</italic>555.
- Author
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Oda, Akiya, Nagao, Satoshi, Yamanaka, Masaru, Ueda, Ikki, Watanabe, Hiroki, Uchihashi, Takayuki, Shibata, Naoki, Higuchi, Yoshiki, and Hirota, Shun
- Subjects
- *
BIOMATERIALS , *CYTOCHROMES , *PROTEIN structure , *INTERMOLECULAR interactions , *TETRAHEDRA - Abstract
Abstract: Highly‐ordered protein structures have gained interest for future uses for biomaterials. Herein, we constructed a building block protein (BBP) by the circular permutation of the hyperthermostable
Aquifex aeolicus cytochrome (cyt)c 555, and assembled BBP into a triangle‐shaped trimer and a tetrahedron. The angle of the intermolecular interactions of BBP was controlled by cleaving the domain‐swapping hinge loop of cytc 555 and connecting the original N‐ and C‐terminal α‐helices with an α‐helical linker. We obtained BBP oligomers up to ≈40 mers, with a relatively large amount of trimers. According to the X‐ray crystallographic analysis of the BBP trimer, the N‐terminal region of one BBP molecule interacted intermolecularly with the C‐terminal region of another BBP molecule, resulting in a triangle‐shaped structure with an edge length of 68 Å. Additionally, four trimers assembled into a unique tetrahedron in the crystal. These results demonstrate that the circular permutation connecting the original N‐ and C‐terminal α‐helices with an α‐helical linker may be useful for constructing organized protein structures. [ABSTRACT FROM AUTHOR]- Published
- 2018
- Full Text
- View/download PDF
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