27 results on '"Satwik Kamtekar"'
Search Results
2. Discovery of Clinical Candidate 1-{[(2S,3S,4S)-3-Ethyl-4-fluoro-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide (PF-06650833), a Potent, Selective Inhibitor of Interleukin-1 Receptor Associated Kinase 4 (IRAK4), by Fragment-Based Drug Design
- Author
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Lori Krim Gavrin, David Hepworth, Jennifer R. Thomason, Iain Kilty, Joel Adam Goldberg, Christoph W. Zapf, Vikram R. Rao, Brian P. Boscoe, Akshay Patny, Peter T. Symanowicz, Marina W.H. Shen, Kevin J. Curran, Elizabeth Murphy, Martin Hegen, Fabien Vincent, Richard Vargas, Satwik Kamtekar, Heidi M. Morgan, Heidi R. Hope, Richard K. Frisbie, Jeanne S. Chang, Ken Dower, Susan E. Drozda, Strohbach Joseph Walter, Mathias John Paul, David R. Anderson, Jacqueline E. Day, Stephen W. Wright, Ivan J. Samardjiev, Seungil Han, Julia H Shin, Frank Lovering, Andrea G Bree, Arthur Lee, Holly H. Soutter, Joanne Brodfuehrer, John David Trzupek, Brian Samas, Christoph Martin Dehnhardt, Michael Dennis Lowe, Catherine M. Ambler, Seung Won Chung, Eddine Saiah, Nikolaos Papaioannou, Pierce Betsy S, Jiangli Yan, Katherine L. Lee, Lih-Ling Lin, and Chulho Choi
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Models, Molecular ,0301 basic medicine ,Lactams ,Stereochemistry ,medicine.drug_class ,Administration, Oral ,Carboxamide ,Structure-Activity Relationship ,03 medical and health sciences ,Drug Discovery ,medicine ,Humans ,Structure–activity relationship ,Protein Kinase Inhibitors ,ADME ,Dose-Response Relationship, Drug ,Molecular Structure ,biology ,Drug discovery ,Chemistry ,Active site ,Isoquinolines ,IRAK4 ,Combinatorial chemistry ,Interleukin-1 Receptor-Associated Kinases ,030104 developmental biology ,Lipophilic efficiency ,Lipophilicity ,biology.protein ,Molecular Medicine - Abstract
Through fragment-based drug design focused on engaging the active site of IRAK4 and leveraging three-dimensional topology in a ligand-efficient manner, a micromolar hit identified from a screen of a Pfizer fragment library was optimized to afford IRAK4 inhibitors with nanomolar potency in cellular assays. The medicinal chemistry effort featured the judicious placement of lipophilicity, informed by co-crystal structures with IRAK4 and optimization of ADME properties to deliver clinical candidate PF-06650833 (compound 40). This compound displays a 5-unit increase in lipophilic efficiency from the fragment hit, excellent kinase selectivity, and pharmacokinetic properties suitable for oral administration.
- Published
- 2017
3. Phi29 DNA polymerase: structure and sequencing
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Satwik Kamtekar
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Inorganic Chemistry ,biology ,Structural Biology ,Chemistry ,DNA polymerase ,biology.protein ,General Materials Science ,Physical and Theoretical Chemistry ,Condensed Matter Physics ,Biochemistry ,Molecular biology - Published
- 2019
4. Crystal structure of an intermediate of rotating dimers within the synaptic tetramer of the G-segment invertase
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Thomas A. Steitz, Satwik Kamtekar, C. Ritacco, and Jimin Wang
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Models, Molecular ,Protein Conformation ,Protein subunit ,Dimer ,Biology ,Crystallography, X-Ray ,law.invention ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,D-loop ,Protein structure ,Tetramer ,Structural Biology ,law ,Genetics ,Site-specific recombination ,030304 developmental biology ,0303 health sciences ,Molecular biology ,Protein Subunits ,chemistry ,DNA Nucleotidyltransferases ,Recombinant DNA ,Biophysics ,Dimerization ,030217 neurology & neurosurgery ,DNA - Abstract
The serine family of site-specific DNA recombination enzymes accomplishes strand cleavage, exchange and religation using a synaptic protein tetramer. A double-strand break intermediate in which each protein subunit is covalently linked to the target DNA substrate ensures that the recombination event will not damage the DNA. The previous structure of a tetrameric synaptic complex of γδ resolvase linked to two cleaved DNA strands had suggested a rotational mechanism of recombination in which one dimer rotates 180° about the flat exchange interface for strand exchange. Here, we report the crystal structure of a synaptic tetramer of an unliganded activated mutant (M114V) of the G-segment invertase (Gin) in which one dimer half is rotated by 26° or 154° relative to the other dimer when compared with the dimers in the synaptic complex of γδ resolvase. Modeling shows that this rotational orientation of Gin is not compatible with its being able to bind uncleaved DNA, implying that this structure represents an intermediate in the process of strand exchange. Thus, our structure provides direct evidence for the proposed rotational mechanism of site-specific recombination.
- Published
- 2012
5. Structural basis of substrate discrimination and integrin binding by autotaxin
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Lyle E. Pegg, Jens Hausmann, Harald M. H. G. Albers, Leonie van Zeijl, Karl Harlos, Wouter H. Moolenaar, Susan S. Smyth, Evangelos Christodoulou, Jacqueline E. Day, Craig W. Vander Kooi, Mobien Kasiem, Andrew J. Morris, Timothy E. Benson, Anna J. S. Houben, Anastassis Perrakis, Maria Andries, Zachary Fulkerson, Mathieu Bollen, Tao Wu, Silvia Jansen, Satwik Kamtekar, Troii Hall, Laurens A. van Meeteren, and Huib Ovaa
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0303 health sciences ,biology ,Phosphatase ,Integrin ,Plasma protein binding ,Lipid signaling ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,chemistry ,Biochemistry ,Structural Biology ,030220 oncology & carcinogenesis ,Lysophosphatidic acid ,biology.protein ,lipids (amino acids, peptides, and proteins) ,Autotaxin ,Binding site ,Molecular Biology ,030304 developmental biology ,Integrin binding - Abstract
Autotaxin (ATX, also known as ectonucleotide pyrophosphatase/phosphodiesterase-2, ENPP2) is a secreted lysophospholipase D that generates the lipid mediator lysophosphatidic acid (LPA), a mitogen and chemoattractant for many cell types. ATX-LPA signaling is involved in various pathologies including tumor progression and inflammation. However, the molecular basis of substrate recognition and catalysis by ATX and the mechanism by which it interacts with target cells are unclear. Here, we present the crystal structure of ATX, alone and in complex with a small-molecule inhibitor. We have identified a hydrophobic lipid-binding pocket and mapped key residues for catalysis and selection between nucleotide and phospholipid substrates. We have shown that ATX interacts with cell-surface integrins through its N-terminal somatomedin B-like domains, using an atypical mechanism. Our results define determinants of substrate discrimination by the ENPP family, suggest how ATX promotes localized LPA signaling and suggest new approaches for targeting ATX with small-molecule therapeutic agents.
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- 2011
6. Structure of the RAG1 nonamer binding domain with DNA reveals a dimer that mediates DNA synapsis
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C.A. Innis, Thomas A. Steitz, David G. Schatz, Mihai Ciubotaru, Satwik Kamtekar, F.F. Yin, and Scott Bailey
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Models, Molecular ,Materials science ,HMG-box ,Dimer ,Amino Acid Motifs ,Molecular Sequence Data ,Static Electricity ,chemical and pharmacologic phenomena ,Crystallography, X-Ray ,Article ,Recombination-activating gene ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Structural Biology ,Fluorescence Resonance Energy Transfer ,Animals ,Amino Acid Sequence ,Protein Structure, Quaternary ,Molecular Biology ,Gene ,030304 developmental biology ,Homeodomain Proteins ,0303 health sciences ,Base Sequence ,Synapsis ,hemic and immune systems ,DNA ,DNA-binding domain ,Protein Structure, Tertiary ,Solutions ,Chromosome Pairing ,chemistry ,Biochemistry ,030220 oncology & carcinogenesis ,Biophysics ,Nucleic Acid Conformation ,Protein Multimerization ,Binding domain - Abstract
The products of recombination-activating genes RAG1 and RAG2 mediate the assembly of antigen receptor genes during lymphocyte development in a process known as V(D)J recombination. Lack of structural information for the RAG proteins has hindered mechanistic studies of this reaction. We report here the crystal structure of an essential DNA binding domain of the RAG1 catalytic core bound to its nonamer DNA recognition motif. The RAG1 nonamer binding domain (NBD) forms a tightly interwoven dimer that binds and synapses two nonamer elements, with each NBD making contact with both DNA molecules. Biochemical and biophysical experiments confirm that the two nonamers are in close proximity in the RAG1/2-DNA synaptic complex and demonstrate the functional importance of the protein-DNA contacts revealed in the structure. These findings reveal a previously unsuspected function for the NBD in DNA synapsis and have implications for the regulation of DNA binding and cleavage by RAG1 and RAG2.
- Published
- 2009
7. Discovery and Characterization of a Highly Selective FAAH Inhibitor that Reduces Inflammatory Pain
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Mauro Mileni, Stephen Swaney, Eranthie Weerapana, Benjamin F. Cravatt, Marya Liimatta, Michele K. McKinney, Sarah E. Smith, Lazerwith Scott E, Nalini Sadagopan, David Beidler, Cory Michael Stiff, Satwik Kamtekar, Douglas S. Johnson, Keri Van Becelaere, Keshab Bhattacharya, Yanhua Zhang, Jonathan Z. Long, Kay Ahn, and Raymond C. Stevens
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Male ,Polyunsaturated Alkamides ,medicine.medical_treatment ,Clinical Biochemistry ,Pain ,Arachidonic Acids ,Pharmacology ,Crystallography, X-Ray ,Biochemistry ,MOLNEURO ,Article ,Piperazines ,Amidohydrolases ,Rats, Sprague-Dawley ,Structure-Activity Relationship ,chemistry.chemical_compound ,Piperidines ,Fatty acid amide hydrolase ,In vivo ,Drug Discovery ,medicine ,Animals ,Humans ,Urea ,Enzyme Inhibitors ,Receptors, Cannabinoid ,Piperazine ,Molecular Biology ,JZL184 ,Brain ,General Medicine ,Anandamide ,Lipid signaling ,ABHD6 ,Endocannabinoid system ,Rats ,CHEMBIO ,nervous system ,chemistry ,Molecular Medicine ,lipids (amino acids, peptides, and proteins) ,Cannabinoid ,psychological phenomena and processes ,Endocannabinoids - Abstract
SummaryEndocannabinoids are lipid signaling molecules that regulate a wide range of mammalian behaviors, including pain, inflammation, and cognitive/emotional state. The endocannabinoid anandamide is principally degraded by the integral membrane enzyme fatty acid amide hydrolase (FAAH), and there is currently much interest in developing FAAH inhibitors to augment endocannabinoid signaling in vivo. Here, we report the discovery and detailed characterization of a highly efficacious and selective FAAH inhibitor, PF-3845. Mechanistic and structural studies confirm that PF-3845 is a covalent inhibitor that carbamylates FAAH's serine nucleophile. PF-3845 selectively inhibits FAAH in vivo, as determined by activity-based protein profiling; raises brain anandamide levels for up to 24 hr; and produces significant cannabinoid receptor-dependent reductions in inflammatory pain. These data thus designate PF-3845 as a valuable pharmacological tool for in vivo characterization of the endocannabinoid system.
- Published
- 2009
8. Asymmetric behavior of archaeal prolyl-tRNA synthetase
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Dieter Söll, Constantinos Stathopoulos, Dexter Kennedy, Alexandre Ambrogelly, and Satwik Kamtekar
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Archaeal Proteins ,Dimer ,Biophysics ,Aminoacylation ,RNA, Transfer, Amino Acyl ,Prolyl tRNA synthetase ,Biochemistry ,Amino Acyl-tRNA Synthetases ,chemistry.chemical_compound ,Structural Biology ,Genetics ,tRNA ,Molecular Biology ,Sequence Deletion ,chemistry.chemical_classification ,Binding Sites ,biology ,Nucleotides ,Methanococcales ,Half-of-the-site reactivity ,Methanocaldococcus jannaschii ,Cell Biology ,biology.organism_classification ,Prolyl-tRNA synthetase ,TRNA binding ,ProRS ,Stoichiometry ,Protein Structure, Tertiary ,Amino acid ,Enzyme ,chemistry ,Transfer RNA ,Transfer RNA Aminoacylation ,Dimerization - Abstract
Archaeal prolyl-tRNA synthetases differ from their bacterial counterparts: they contain an additional domain (about 70 amino acids) appended to the carboxy-terminus and lack an editing domain inserted into the class II catalytic core. Biochemical and structural approaches have generated a wealth of information on amino acid and tRNA specificities for both types of ProRSs, but have left a number of aspects unexplored. We report here that the carboxy-terminal domain of Methanocaldococcus jannaschii ProRS is not involved in tRNA binding since its deletion only mildly affects the kinetic parameters for the enzyme. We also demonstrate that M. jannaschii ProRS is a homodimeric enzyme that is functionally asymmetric; only one of the two active sites at a time is able to form prolyl-adenylate, and only one tRNA molecule binds per dimer. Together with previous reports our results show that asymmetry might be a general feature of the aminoacylation reaction catalyzed by dimeric aminoacyl-tRNA synthetases from both classes.
- Published
- 2005
9. Structure of a Synaptic γδ Resolvase Tetramer Covalently Linked to Two Cleaved DNAs
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Gary J. Sarkis, Weikai Li, Satwik Kamtekar, Nigel D. F. Grindley, Yong Xiong, and Thomas A. Steitz
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Models, Molecular ,Tn3 transposon ,Stereochemistry ,Dimer ,Biology ,Crystallography, X-Ray ,Cleavage (embryo) ,Protein Structure, Secondary ,chemistry.chemical_compound ,Tetramer ,Catalytic Domain ,Recombinase ,Computer Simulation ,Site-specific recombination ,Protein Structure, Quaternary ,Recombination, Genetic ,Binding Sites ,Multidisciplinary ,DNA ,Protein Structure, Tertiary ,Crystallography ,Amino Acid Substitution ,chemistry ,Duplex (building) ,Mutation ,Transposon Resolvases ,Dimerization - Abstract
The structure of a synaptic intermediate of the site-specific recombinase γδ resolvase covalently linked through Ser 10 to two cleaved duplex DNAs has been determined at 3.4 angstrom resolution. This resolvase, activated for recombination by mutations, forms a tetramer whose structure is substantially changed from that of a presynaptic complex between dimeric resolvase and the cleavage site DNA. Because the two cleaved DNA duplexes that are to be recombined lie on opposite sides of the core tetramer, large movements of both protein and DNA are required to achieve strand exchange. The two dimers linked to the DNAs that are to be recombined are held together by a flat interface. This may allow a 180° rotation of one dimer relative to the other in order to reposition the DNA duplexes for strand exchange.
- Published
- 2005
10. A specific subdomain in φ29 DNA polymerase confers both processivity and strand-displacement capacity
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Andrea J. Berman, Satwik Kamtekar, José M. Lázaro, Thomas A. Steitz, Margarita Salas, Miguel de Vega, Irene Rodríguez, Jimin Wang, Luis Blanco, Ministerio de Ciencia y Tecnología (España), National Institutes of Health (US), Fundación Ramón Areces, and Consejo Superior de Investigaciones Científicas (España)
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DNA Replication ,Models, Molecular ,Protein Conformation ,DNA polymerase ,DNA polymerase II ,Molecular Sequence Data ,Electrophoretic Mobility Shift Assay ,DNA-Directed DNA Polymerase ,DNA polymerase delta ,DNA-binding stability ,Bacteriophage T4 ,Amino Acid Sequence ,Polymerase ,DNA Primers ,Transcription bubble ,Multidisciplinary ,DNA clamp ,Helicase-like activity ,biology ,DNA ,Templates, Genetic ,Processivity ,Biological Sciences ,Protein Structure, Tertiary ,Terminal protein region ,Exodeoxyribonucleases ,Biochemistry ,Mutagenesis, Site-Directed ,biology.protein ,Biophysics ,Primer (molecular biology) ,Sequence Alignment ,Protein-primed replication - Abstract
Recent crystallographic studies of φ29 DNA polymerase have provided structural insights into its strand displacement and processivity. A specific insertion named terminal protein region 2 (TPR2), present only in protein-primed DNA polymerases, together with the exonuclease, thumb, and palm subdomains, forms two tori capable of interacting with DNA. To analyze the functional role of this insertion, we constructed a φ29 DNA polymerase deletion mutant lacking TPR2 amino acid residues Asp-398 to Glu-420. Biochemical analysis of the mutant DNA polymerase indicates that its DNA-binding capacity is diminished, drastically decreasing its processivity. In addition, removal of the TPR2 insertion abolishes the intrinsic capacity of φ29 DNA polymerase to perform strand displacement coupled to DNA synthesis. Therefore, the biochemical results described here directly demonstrate that TPR2 plays a critical role in strand displacement and processivity., This investigation was aided by Research Grant BMC 2002-03818 from the Spanish Ministry of Science and Technology (to M.S.), Grant R01GM57510 from the National Institutes of Health (to T.A.S.), and an institutional grant from Fundación Ramón Areces to the Centro de Biología Molecular “Severo Ochoa.” I.R. was a predoctoral fellow of the Consejo Superior de Investigaciones Científicas.
- Published
- 2005
11. Correction of X-ray intensities from single crystals containing lattice-translocation defects
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Andrea J. Berman, Thomas A. Steitz, Satwik Kamtekar, and Jimin Wang
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Models, Molecular ,Diffraction ,Multiple isomorphous replacement ,Macromolecular Substances ,Protein Conformation ,Molecular Conformation ,Bacillus Phages ,DNA-Directed DNA Polymerase ,Crystal structure ,Crystallography, X-Ray ,Molecular physics ,law.invention ,X-Ray Diffraction ,Structural Biology ,law ,Lattice (order) ,Crystallization ,Models, Statistical ,Chemistry ,X-Rays ,X-ray ,General Medicine ,Crystallography ,Amplitude ,X-ray crystallography ,Software - Abstract
In 1954, Howells and colleagues described an unusual diffraction pattern from imidazole methemoglobin crystals caused by lattice-translocation defects. In these crystals, two identical lattices coexist as a single coherent mosaic block, but are translated by a fixed vector with respect to each other. The observed structure is a weighted sum of the two identical but translated structures, one from each lattice; the observed structure factors are a weighted vector sum of the two structure factors with identical unit amplitudes but shifted phases. A general procedure is described to obtain the unit amplitudes of observed structure factors from a realigned single lattice through an X-ray intensity correction. An application of this procedure is made to determine the crystal structure of phi29 DNA polymerase at 2.2 A resolution using multiple isomorphous replacement and multiwavelength anomalous dispersion methods.
- Published
- 2004
12. Insights into Strand Displacement and Processivity from the Crystal Structure of the Protein-Primed DNA Polymerase of Bacteriophage φ29
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Andrea J. Berman, José M. Lázaro, Margarita Salas, Jimin Wang, Luis Blanco, Thomas A. Steitz, Miguel de Vega, Satwik Kamtekar, National Institutes of Health (US), Ministerio de Economía y Competitividad (España), and Fundación Ramón Areces
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Models, Molecular ,DNA polymerase ,DNA polymerase II ,Static Electricity ,DNA, Single-Stranded ,Bacillus Phages ,DNA-Directed DNA Polymerase ,Crystallography, X-Ray ,Models, Biological ,DNA polymerase delta ,Bacteriophage T7 ,Amino Acid Sequence ,Molecular Biology ,Polymerase ,Transcription bubble ,Binding Sites ,DNA clamp ,Base Sequence ,biology ,DNA replication ,Templates, Genetic ,Processivity ,Cell Biology ,Molecular biology ,Protein Structure, Tertiary ,Mutation ,biology.protein - Abstract
The DNA polymerase from phage φ29 is a B family polymerase that initiates replication using a protein as a primer, attaching the first nucleotide of the phage genome to the hydroxyl of a specific serine of the priming protein. The crystal structure of φ29 DNA polymerase determined at 2.2 Å resolution provides explanations for its extraordinary processivity and strand displacement activities. Homology modeling suggests that downstream template DNA passes through a tunnel prior to entering the polymerase active site. This tunnel is too small to accommodate double-stranded DNA and requires the separation of template and nontemplate strands. Members of the B family of DNA polymerases that use protein primers contain two sequence insertions: one forms a domain not previously observed in polymerases, while the second resembles the specificity loop of T7 RNA polymerase. The high processivity of φ29 DNA polymerase may be explained by its topological encirclement of both the downstream template and the upstream duplex DNA., This work was funded in part by grant R01GM57510 from the National Institutes for Health to T.A.S., by grants BMC2002-03818 from the Dirección General de Investigación Cientı́fica y Técnica and 2R01 GM27242-24 from the National Institutes for Health to M.S., and by an institutional grant from Fundación Ramón Areces to the Centro de Biologı́a Molecular “Severo Ochoa.”
- Published
- 2004
- Full Text
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13. Cys-tRNACys formation and cysteine biosynthesis in methanogenic archaea: two faces of the same problem?
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Ivan Ahel, Benfang Ruan, Anselm Sauerwald, Debra Tumbula-Hansen, D Kennedy, Dieter Söll, Alexandre Ambrogelly, and Satwik Kamtekar
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Models, Molecular ,Protein Conformation ,RNA, Transfer, Amino Acyl ,Models, Biological ,Ribosome ,Genes, Archaeal ,Cellular and Molecular Neuroscience ,Cys-trna(cys) ,Cysteine biosynthesis ,Cysteinyl-trna synthetase ,Archaea ,Methanogens ,Protein biosynthesis ,Cysteine ,Molecular Biology ,Gene ,Phylogeny ,Pharmacology ,Genetics ,Binding Sites ,biology ,RNA ,Methanocaldococcus jannaschii ,Translation (biology) ,Cell Biology ,biology.organism_classification ,Biochemistry ,Protein Biosynthesis ,Transfer RNA ,Molecular Medicine ,Methane - Abstract
Aminoacyl-tRNA ( transfer RNA) synthetases are essential components of the cellular translation machinery as they provide the ribosome with aminoacyl-tRNAs. Aminoacyl-tRNA synthesis is generally well understood. However, the mechanism of Cys-tRNACys formation in three methanogenic archaea (Methanocaldococcus jannaschii, Methanothermobacter thermautotrophicus and Methanopyrus kandleri) is still unknown, since no recognizable gene for a canonical cysteinyl-tRNA synthetase could be identified in the genome sequences of these organisms. Here we review the different routes recently proposed for Cys-tRNA(Cys) formation and discuss its possible link with cysteine biosynthesis in these methanogenic archaea.
- Published
- 2004
14. Nucleotide-Dependent Conformational Changes in a Protease-Associated ATPase HslU
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J.J. Song, Jimin Wang, Ihn Sik Seong, Chin Ha Chung, Matthew C. Franklin, Satwik Kamtekar, and Soo Hyun Eom
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Models, Molecular ,Conformational change ,Protein Denaturation ,translocation mechanism ,hexameric ATPase ,Protein Conformation ,ATPase ,medicine.medical_treatment ,HslVU ,03 medical and health sciences ,ATP-Dependent Proteases ,Phenols ,Structural Biology ,Endopeptidases ,medicine ,Nucleotide ,Molecular Biology ,Heat-Shock Proteins ,030304 developmental biology ,chemistry.chemical_classification ,Adenosine Triphosphatases ,0303 health sciences ,Protease ,biology ,Adenine Nucleotides ,C-terminus ,030302 biochemistry & molecular biology ,Serine Endopeptidases ,nucleotide-dependent motions ,Hydrazones ,Biological activity ,Biological Transport ,Adenosine Diphosphate ,Biochemistry ,chemistry ,Chaperone (protein) ,biology.protein ,Biophysics - Abstract
Background : The bacterial heat shock locus ATPase HslU is an AAA + protein that has structures known in many nucleotide-free and -bound states. Nucleotide is required for the formation of the biologically active HslU hexameric assembly. The hexameric HslU ATPase binds the dodecameric HslV peptidase and forms an ATP-dependent HslVU protease. Results: We have characterized four distinct HslU conformational states, going sequentially from open to closed: the empty, SO 4 , ATP, and ADP states. The nucleotide binds at a cleft formed by an α/β domain and an α-helical domain in HslU. The four HslU states differ by a rotation of the α-helical domain. This classification leads to a correction of nucleotide identity in one structure and reveals the ATP hydrolysis-dependent structural changes in the HslVU complex, including a ring rotation and a conformational change of the HslU C terminus. This leads to an amended protein unfolding-coupled translocation mechanism. Conclusions: The observed nucleotide-dependent conformational changes in HslU and their governing principles provide a framework for the mechanistic understanding of other AAA + proteins.
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- 2001
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15. Crystal Structures of the HslVU Peptidase–ATPase Complex Reveal an ATP-Dependent Proteolysis Mechanism
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Ihn Sik Seong, Y.J. Im, Satwik Kamtekar, Jimin Wang, Matthew C. Franklin, J.J. Song, Soo Hyun Eom, C.S. Lee, Seong-Hwan Rho, and Chin Ha Chung
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Models, Molecular ,ATPase ,Molecular Sequence Data ,Molecular Conformation ,translocation ,HslVU ,Random hexamer ,Crystallography, X-Ray ,Adenosine Triphosphate ,Protein structure ,ATP-Dependent Proteases ,Structural Biology ,Endopeptidases ,Amino Acid Sequence ,Protein Structure, Quaternary ,Molecular Biology ,Conserved Sequence ,Heat-Shock Proteins ,Adenosine Triphosphatases ,biology ,ATP-dependent proteolysis ,protein unfolding ,Serine Endopeptidases ,ATPase complex ,Adenosine Diphosphate ,Dodecameric protein ,Proteasome ,Biochemistry ,biology.protein ,Biophysics - Abstract
Background: The bacterial h eat s hock l ocus HslU ATPase and HslV peptidase together form an ATP-dependent HslVU protease. Bacterial HslVU is a homolog of the eukaryotic 26S proteasome. Crystallographic studies of HslVU should provide an understanding of ATP-dependent protein unfolding, translocation, and proteolysis by this and other ATP-dependent proteases. Results: We present a 3.0 A resolution crystal structure of HslVU with an HslU hexamer bound at one end of an HslV dodecamer. The structure shows that the central pores of the ATPase and peptidase are next to each other and aligned. The central pore of HslU consists of a GYVG motif, which is conserved among protease-associated ATPases. The binding of one HslU hexamer to one end of an HslV dodecamer in the 3.0 A resolution structure opens both HslV central pores and induces asymmetric changes in HslV. Conclusions: Analysis of nucleotide binding induced conformational changes in the current and previous HslU structures suggests a protein unfolding–coupled translocation mechanism. In this mechanism, unfolded polypeptides are threaded through the aligned pores of the ATPase and peptidase and translocated into the peptidase central chamber.
- Published
- 2001
- Full Text
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16. The four‐lielix bundle: what determines a fold?
- Author
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Michael H. Hecht and Satwik Kamtekar
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Helix bundle ,Chemistry ,Fold (geology) ,Conformational entropy ,Biochemistry ,DNA-binding protein ,Protein structure ,Bundle ,Genetics ,Biophysics ,Protein folding ,Structural motif ,Molecular Biology ,Biotechnology - Abstract
The four-helix bundle motif occurs in many structural contexts and in proteins that are functionally diverse. The motif can be classified into individual folds on the basis of topological and geometric properties. It has been thoroughly investigated structurally by both nuclear magnetic resonance and x-ray crystallography. Many mutants of four-helix bundles have been generated, and the motif has also been the target of de novo design studies. Taken together, these studies provide an opportunity to examine many of the forces governing protein folding. In this article we consider the relative importance of the burial of hydrophobic residues, loss of conformational entropy, packing interactions, interhelical turn composition, and helical dipole interactions all within the context of a single folding motif. We conclude by examining why de novo designed four-helix bundle proteins possess flexible interiors, and possible mechanisms by which natural proteins may lock their cores into rigid structures.
- Published
- 1995
17. Discovery of novel spirocyclic inhibitors of fatty acid amide hydrolase (FAAH). Part 2. Discovery of 7-azaspiro[3.5]nonane urea PF-04862853, an orally efficacious inhibitor of fatty acid amide hydrolase (FAAH) for pain
- Author
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Sarah E. Smith, Marvin J. Meyers, Young-Sun Yang, Joseph J. McDonald, David Beidler, Atli Thorarensen, Matthew James Pelc, Jeanne M. Rumsey, Mark V. Wilcox, Satwik Kamtekar, Scott A. Long, Scott J. Bowen, Jane L. Wang, Mark C. Walker, Susan Foltin, and Barbara A. Schweitzer
- Subjects
Stereochemistry ,Clinical Biochemistry ,Drug Evaluation, Preclinical ,Pharmaceutical Science ,Administration, Oral ,Biological Availability ,Pain ,Biochemistry ,Amidase ,Amidohydrolases ,chemistry.chemical_compound ,Fatty acid amide hydrolase ,In vivo ,Drug Discovery ,Animals ,Spiro Compounds ,Enzyme Inhibitors ,Molecular Biology ,Chromatography, High Pressure Liquid ,Analgesics ,Aza Compounds ,Fatty acid amide ,biology ,Chemistry ,Organic Chemistry ,Serine hydrolase ,Anandamide ,Endocannabinoid system ,Rats ,Enzyme inhibitor ,biology.protein ,Molecular Medicine - Abstract
Fatty acid amide hydrolase (FAAH) is an integral membrane serine hydrolase responsible for the degradation of fatty acid amide signaling molecules such as endocannabinoid anandamide (AEA), which has been shown to possess cannabinoid-like analgesic properties. Herein we report the optimization of spirocyclic 7-azaspiro[3.5]nonane and 1-oxa-8-azaspiro[4.5]decane urea covalent inhibitors of FAAH. Using an iterative design and optimization strategy, lead compounds were identified with a remarkable reduction in molecular weight and favorable CNS drug like properties. 3,4-Dimethylisoxazole and 1-methyltetrazole were identified as superior urea moieties for this inhibitor class. A dual purpose in vivo efficacy and pharmacokinetic screen was designed to be the key decision enabling experiment affording the ability to move quickly from compound synthesis to selection of preclinical candidates. On the basis of the remarkable potency, selectivity, pharmacokinetic properties and in vivo efficacy, PF-04862853 (15p) was advanced as a clinical candidate.
- Published
- 2011
18. Crystallization and preliminary X-ray diffraction analysis of rat autotaxin
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Troii Hall, Jacqueline E. Day, Jens Hausmann, Lyle E. Pegg, Satwik Kamtekar, and Timothy E. Benson
- Subjects
Phosphoric Diester Hydrolases ,Biophysics ,Condensed Matter Physics ,Crystallography, X-Ray ,Biochemistry ,Ammonium iodide ,law.invention ,Rats ,Solvent ,Crystallography ,chemistry.chemical_compound ,chemistry ,Structural Biology ,law ,Crystallization Communications ,PEG ratio ,X-ray crystallography ,Genetics ,Molecule ,Animals ,Sodium thiocyanate ,Crystallization ,Autotaxin ,Pyrophosphatases - Abstract
Rat autotaxin has been cloned, expressed, purified to homogeneity and crystallizedviahanging-drop vapour diffusion using PEG 3350 as precipitant and ammonium iodide and sodium thiocyanate as salts. The crystals diffracted to a maximum resolution of 2.05 Å and belonged to space groupP1, with unit-cell parametersa= 53.8,b= 63.3,c= 70.5 Å, α = 98.8, β = 106.2, γ = 99.8°. Preliminary X-ray diffraction analysis indicated the presence of one molecule per asymmetric unit, with a solvent content of 47%.
- Published
- 2010
19. ChemInform Abstract: Protein Design by Binary Patterning of Polar and Nonpolar Amino Acids
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Huayu Xiong, Jarad M. Schiffer, Satwik Kamtekar, Michael H. Hecht, and Jennifer M. Babik
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chemistry.chemical_classification ,chemistry ,Stereochemistry ,Protein design ,Side chain ,Polar ,Binary code ,Sequence (biology) ,General Medicine ,Peptide sequence ,Gene ,Amino acid - Abstract
A general strategy is described for the de novo design of proteins. In this strategy the sequence locations of hydrophobic and hydrophilic residues were specified explicitly, but the precise identities of the side chains were not constrained and varied extensively. This strategy was tested by constructing a large collection of synthetic genes whose protein products were designed to fold into four-helix bundle proteins. Each gene encoded a different amino acid sequence, but all sequences shared the same pattern of polar and nonpolar residues. Characterization of the expressed proteins indicated that most of the designed sequences folded into compact alpha-helical structures. Thus, a simple binary code of polar and nonpolar residues arranged in the appropriate order can drive polypeptide chains to collapse into globular alpha-helical folds.
- Published
- 2010
20. Kinetic and structural characterization of caspase-3 and caspase-8 inhibition by a novel class of irreversible inhibitors
- Author
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Robert L. Heinrikson, Zhigang Wang, James Robert Blinn, Arthur J. Wittwer, Douglas P. Boatman, Alfredo G. Tomasselli, Michael Kahn, Jan Urban, Melissa S. Harris, Barry C. Finzel, Nathan A. Brooks, Satwik Kamtekar, W. Watt, and Michael McMillan
- Subjects
Programmed cell death ,Peptidomimetic ,Protein Conformation ,Allosteric regulation ,Biophysics ,Caspase 3 ,Cysteine Proteinase Inhibitors ,Caspase 8 ,Crystallography, X-Ray ,Biochemistry ,Analytical Chemistry ,Protein structure ,Humans ,Molecular Biology ,Caspase ,biology ,Molecular Structure ,Chemistry ,Small molecule ,Caspase Inhibitors ,Kinetics ,biology.protein ,Crystallization - Abstract
Because of their central role in programmed cell death, the caspases are attractive targets for developing new therapeutics against cancer and autoimmunity, myocardial infarction and ischemic damage, and neurodegenerative diseases. We chose to target caspase-3, an executioner caspase, and caspase-8, an initiator caspase, based on the vast amount of information linking their functions to diseases. Through a structure-based drug design approach, a number of novel beta-strand peptidomimetic compounds were synthesized. Kinetic studies of caspase-3 and caspase-8 inhibition were carried out with these urazole ring-containing irreversible peptidomimetics and a known irreversible caspase inhibitor, Z-VAD-fmk. Using a stopped-flow fluorescence assay, we were able to determine individual kinetic parameters of caspase-3 and caspase-8 inhibition by these inhibitors. Z-VAD-fmk and the peptidomimetic inhibitors inhibit caspase-3 and caspase-8 via a three-step kinetic mechanism. Inhibition of both caspase-3 and caspase-8 by Z-VAD-fmk and of caspase-3 by the peptidomimetic inhibitors proceeds via two rapid equilibrium steps followed by a relatively fast inactivation step. However, caspase-8 inhibition by the peptidomimetics goes through a rapid equilibrium step, a slow-binding reversible step, and an extremely slow inactivation step. The crystal structures of inhibitor complexes of caspases-3 and -8 validate the design of the inhibitors by illustrating in detail how they mimic peptide substrates. One of the caspase-8 structures also shows binding at a secondary, allosteric site, providing a possible route to the development of noncovalent small molecule modulators of caspase activity.
- Published
- 2010
21. Structure-guided inhibitor design for human FAAH by interspecies active site conversion
- Author
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Mauro Mileni, Benjamin F. Cravatt, Marya Liimatta, Douglas S. Johnson, Richard A. Nugent, Daniel S. Everdeen, Satwik Kamtekar, Raymond C. Stevens, Keshab Bhattacharya, Zhigang Wang, Kay Ahn, and Brandon Pabst
- Subjects
Models, Molecular ,Crystallography, X-Ray ,Protein Engineering ,Catalysis ,Protein Structure, Secondary ,Amidohydrolases ,chemistry.chemical_compound ,Piperidines ,Species Specificity ,Fatty acid amide hydrolase ,Hydrolase ,Animals ,Humans ,Anilides ,Binding site ,Enzyme Inhibitors ,chemistry.chemical_classification ,Multidisciplinary ,Binding Sites ,Cannabinoid Receptor Agonists ,Protein engineering ,Anandamide ,Biological Sciences ,Endocannabinoid system ,Rats ,Kinetics ,Enzyme ,chemistry ,Biochemistry ,nervous system ,Drug Design ,lipids (amino acids, peptides, and proteins) ,psychological phenomena and processes - Abstract
The integral membrane enzyme fatty acid amide hydrolase (FAAH) hydrolyzes the endocannabinoid anandamide and related amidated signaling lipids. Genetic or pharmacological inactivation of FAAH produces analgesic, anxiolytic, and antiinflammatory phenotypes but not the undesirable side effects of direct cannabinoid receptor agonists, indicating that FAAH may be a promising therapeutic target. Structure-based inhibitor design has, however, been hampered by difficulties in expressing the human FAAH enzyme. Here, we address this problem by interconverting the active sites of rat and human FAAH using site-directed mutagenesis. The resulting humanized rat (h/r) FAAH protein exhibits the inhibitor sensitivity profiles of human FAAH but maintains the high-expression yield of the rat enzyme. We report a 2.75-Å crystal structure of h/rFAAH complexed with an inhibitor, N -phenyl-4-(quinolin-3-ylmethyl)piperidine-1-carboxamide (PF-750), that shows strong preference for human FAAH. This structure offers compelling insights to explain the species selectivity of FAAH inhibitors, which should guide future drug design programs.
- Published
- 2008
22. Structures of phi29 DNA polymerase complexed with substrate: the mechanism of translocation in B-family polymerases
- Author
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Satwik Kamtekar, Luis Blanco, Jessica L. Goodman, Miguel de Vega, Thomas A. Steitz, Andrea J. Berman, José M. Lázaro, Margarita Salas, National Institutes of Health (US), Ministerio de Educación y Ciencia (España), and Fundación Ramón Areces
- Subjects
Exonucleases ,Models, Molecular ,DNA polymerase ,Amino Acid Motifs ,Chromosomal translocation ,Bacillus Phages ,DNA-Directed DNA Polymerase ,Crystallography, X-Ray ,Article ,General Biochemistry, Genetics and Molecular Biology ,Substrate Specificity ,chemistry.chemical_compound ,Tyrosine ,Molecular Biology ,Polymerase ,General Immunology and Microbiology ,biology ,General Neuroscience ,Water ,Substrate (chemistry) ,Phi29 ,Templates, Genetic ,Transport protein ,Protein Transport ,Biochemistry ,chemistry ,DNA, Viral ,biology.protein ,Nucleoside triphosphate ,DNA - Abstract
Replicative DNA polymerases (DNAPs) move along template DNA in a processive manner. The structural basis of the mechanism of translocation has been better studied in the A-family of polymerases than in the B-family of replicative polymerases. To address this issue, we have determined the X-ray crystal structures of phi29 DNAP, a member of the protein-primed subgroup of the B-family of polymerases, complexed with primer-template DNA in the presence or absence of the incoming nucleoside triphosphate, the pre- and post-translocated states, respectively. Comparison of these structures reveals a mechanism of translocation that appears to be facilitated by the coordinated movement of two conserved tyrosine residues into the insertion site. This differs from the mechanism employed by the A-family polymerases, in which a conserved tyrosine moves into the templating and insertion sites during the translocation step. Polymerases from the two families also interact with downstream single-stranded template DNA in very different ways., This work was supported by NIH grant GM57510 to TAS, grant BFU2005-00733 from the Spanish Ministry of Education and Science to MS and an institutional grant from Fundación Ramón Areces to the Centro de Biología Molecular Severo Ochoa.
- Published
- 2007
23. Implications of structures of synaptic tetramers of gamma delta resolvase for the mechanism of recombination
- Author
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Thomas A. Steitz, Roger S. Ho, Melanie J. Cocco, Sandra V. C. T. Wenwieser, Martin R. Boocock, Weikai Li, Satwik Kamtekar, and Nigel D. F. Grindley
- Subjects
Recombination, Genetic ,Tn3 transposon ,Multidisciplinary ,Transposon Resolvases ,Mutant ,Mutant Chimeric Proteins ,DNA ,Biology ,Biological Sciences ,Crystallography, X-Ray ,Crystallography ,chemistry.chemical_compound ,Tetramer ,chemistry ,DNA Nucleotidyltransferases ,Recombinase ,Biophysics ,Humans ,Site-specific recombination ,Recombination - Abstract
The structures of two mutants of the site-specific recombinase, γδ resolvase, that form activated tetramers have been determined. One, at 3.5-Å resolution, forms a synaptic intermediate of resolvase that is covalently linked to two cleaved DNAs, whereas the other is of an unliganded structure determined at 2.1-Å resolution. Comparisons of the four known tetrameric resolvase structures show that the subunits interact through the formation of a common core of four helices. The N-terminal halves of these helices superimpose well on each other, whereas the orientations of their C termini are more variable. The catalytic domains of resolvase in the unliganded structure are arranged asymmetrically, demonstrating that their positions can move substantially while preserving the four-helix core that forms the tetramer. These results suggest that the precleavage synaptic tetramer of γδ resolvase, whose structure is not known, may be formed by a similar four-helix core, but differ in the relative orientations of its catalytic and DNA-binding domains.
- Published
- 2006
24. The phi29 DNA polymerase:protein-primer structure suggests a model for the initiation to elongation transition
- Author
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Miguel de Vega, Andrea J. Berman, José M. Lázaro, Jimin Wang, Luis Blanco, Margarita Salas, Thomas A. Steitz, Satwik Kamtekar, National Institutes of Health (US), Ministerio de Ciencia y Tecnología (España), and Fundación Ramón Areces
- Subjects
DNA Replication ,Models, Molecular ,Transcription, Genetic ,DNA polymerase ,DNA polymerase II ,Peptide Chain Elongation, Translational ,Bacillus Phages ,DNA-Directed DNA Polymerase ,Crystallography, X-Ray ,General Biochemistry, Genetics and Molecular Biology ,Article ,Molecular Biology ,Polymerase ,DNA Primers ,DNA clamp ,Binding Sites ,General Immunology and Microbiology ,biology ,General Neuroscience ,Molecular biology ,Mutation ,biology.protein ,Primase ,DNA polymerase I ,Primer (molecular biology) ,DNA polymerase mu ,Protein-primed replication - Abstract
The absolute requirement for primers in the initiation of DNA synthesis poses a problem for replicating the ends of linear chromosomes. The DNA polymerase of bacteriophage 29 solves this problem by using a serine hydroxyl of terminal protein to prime replication. The 3.0 Å resolution structure shows one domain of terminal protein making no interactions, a second binding the polymerase and a third domain containing the priming serine occupying the same binding cleft in the polymerase as duplex DNA does during elongation. Thus, the progressively elongating DNA duplex product must displace this priming domain. Further, this heterodimer of polymerase and terminal protein cannot accommodate upstream template DNA, thereby explaining its specificity for initiating DNA synthesis only at the ends of the bacteriophage genome. We propose a model for the transition from the initiation to the elongation phases in which the priming domain of terminal protein moves out of the active site as polymerase elongates the primer strand. The model indicates that terminal protein should dissociate from polymerase after the incorporation of approximately six nucleotides., We were funded by grants R01 GM 57510 from the National Institutes of Health (to TAS) and BMC 2002-03818 from the Spanish Ministry of Science and Technology (to MS), and an institutional grant from Fundación Ramón Areces to the Centro de Biología Molecular 'Severo Ochoa'.
- Published
- 2006
25. The structural basis of cysteine aminoacylation of tRNAPro by prolyl-tRNA synthetases
- Author
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Constantinos Stathopoulos, W.D. Kennedy, Jimin Wang, Dieter Söll, Satwik Kamtekar, and Thomas A. Steitz
- Subjects
chemistry.chemical_classification ,Models, Molecular ,Multidisciplinary ,biology ,Protein Conformation ,Acylation ,Methanocaldococcus jannaschii ,Aminoacylation ,Biological Sciences ,Euryarchaeota ,biology.organism_classification ,Amino acid ,Amino Acyl-tRNA Synthetases ,RNA, Transfer, Pro ,Protein structure ,chemistry ,Biochemistry ,Transfer RNA ,Protein biosynthesis ,Homology modeling ,Cysteine ,Protein Binding - Abstract
Cysteinyl-tRNA synthetase is an essential enzyme required for protein synthesis. Genes encoding this protein have not been identified in Methanocaldococcus jannaschii , Methanothermobacter thermautotrophicus , or Methanopyrus kandleri . It has previously been proposed that the prolyl-tRNA synthetase (ProRS) enzymes in these organisms recognize either proline or cysteine and can aminoacylate their cognate tRNAs through a dual-specificity mechanism. We report five crystal structures at resolutions between 2.6 and 3.2 Å: apo M. jannaschii ProRS, and M. thermautotrophicus ProRS in apo form and in complex with cysteinyl-sulfamoyl-, prolyl-sulfamoyl-, and alanyl-sulfamoyl-adenylates. These aminoacyl-adenylate analogues bind to a single active-site pocket and induce an identical set of conformational changes in loops around the active site when compared with the ligand-free conformation of ProRS. The cysteinyl- and prolyl-adenylate analogues have similar, nanomolar affinities for M. thermautotrophicus ProRS. Homology modeling of tRNA onto these adenylate complexes places the 3′-OH of A76 in an appropriate position for the transfer of any of the three amino acids to tRNA. Thus, these structures explain recent biochemical experiments showing that M. jannaschii ProRS misacylates tRNA Pro with cysteine, and argue against the proposal that these archaeal ProRS enzymes possess the dual capacity to aminoacylate both tRNA Pro and tRNA Cys with their cognate amino acids.
- Published
- 2003
26. De novo heme proteins from designed combinatorial libraries
- Author
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Michael H. Hecht, Kathleen M. Vogel, Thomas G. Spiro, Nina R. L. Rojas, Satwik Kamtekar, Cyrena T. Simons, Jeremy E. Mclean, and Ramy S. Farid
- Subjects
Hemeproteins ,Models, Molecular ,Binding Sites ,Molecular Sequence Data ,Heme ,Spectrum Analysis, Raman ,Biochemistry ,Protein Structure, Secondary ,Drug Stability ,Spectrophotometry ,Drug Design ,Amino Acid Sequence ,Molecular Biology ,Gene Library ,Research Article - Abstract
We previously reported the design of a library of de novo amino acid sequences targeted to fold into four-helix bundles. The design of these sequences was based on a "binary code" strategy, in which the patterning of polar and nonpolar amino acids is specified explicitly, but the exact identities of the side chains is varied extensively (Kamtekar S, Schiffer JM, Xiong H, Babik JM, Hecht MH, 1993, Science 262:1680-1685). Because of this variability, the resulting collection of amino acid sequences may include de novo proteins capable of binding biologically important cofactors. To probe for such binding, the de novo sequences were screened for their ability to bind the heme cofactor. Among an initial collection of 30 binary code sequences, 15 are shown to bind heme and form bright red complexes. Characterization of several of these de novo heme proteins demonstrated that their absorption spectra and resonance Raman spectra resemble those of natural cytochromes. Because the design of these sequences is based on global features of polar/ nonpolar patterning, the finding that half of them bind heme highlights the power of the binary code strategy, and demonstrates that isolating de novo heme proteins does not require explicit design of the cofactor binding site. Because bound heme plays a key role in the functions of many natural proteins, these results suggest that binary code sequences may serve as initial prototypes for the development of large collections of functionally active de novo proteins.
- Published
- 1998
27. Protein design by binary patterning of polar and nonpolar amino acids
- Author
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Huayu Xiong, Jennifer M. Babik, Jarad M. Schiffer, Satwik Kamtekar, and Michael H. Hecht
- Subjects
Protein Folding ,Stereochemistry ,Protein Conformation ,Protein design ,Molecular Sequence Data ,Sequence (biology) ,Biology ,Protein Engineering ,Protein Structure, Secondary ,Protein structure ,Side chain ,Genes, Synthetic ,Amino Acid Sequence ,Codon ,Peptide sequence ,Gene Library ,chemistry.chemical_classification ,Multidisciplinary ,Base Sequence ,Proteins ,Protein engineering ,Amino acid ,Molecular Weight ,chemistry ,Oligodeoxyribonucleotides ,Protein folding - Abstract
A general strategy is described for the de novo design of proteins. In this strategy the sequence locations of hydrophobic and hydrophilic residues were specified explicitly, but the precise identities of the side chains were not constrained and varied extensively. This strategy was tested by constructing a large collection of synthetic genes whose protein products were designed to fold into four-helix bundle proteins. Each gene encoded a different amino acid sequence, but all sequences shared the same pattern of polar and nonpolar residues. Characterization of the expressed proteins indicated that most of the designed sequences folded into compact alpha-helical structures. Thus, a simple binary code of polar and nonpolar residues arranged in the appropriate order can drive polypeptide chains to collapse into globular alpha-helical folds.
- Published
- 1993
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