8 results on '"Chéron JB"'
Search Results
2. Allosteric Modulation Mechanism of the mGluR 5 Transmembrane Domain.
- Author
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Cong X, Chéron JB, Golebiowski J, Antonczak S, and Fiorucci S
- Subjects
- Allosteric Regulation, Humans, Mutation, Protein Domains, Receptor, Metabotropic Glutamate 5 genetics, Cell Membrane metabolism, Molecular Dynamics Simulation, Receptor, Metabotropic Glutamate 5 chemistry, Receptor, Metabotropic Glutamate 5 metabolism
- Abstract
Positive allosteric modulators (PAMs) of metabotropic glutamate receptor type 5 (mGluR
5 ), a prototypical class C G protein-coupled receptor (GPCR), have shown therapeutic potential for various neurological disorders. Understanding the allosteric activation mechanism is essential for the rational design of mGluR5 PAMs. We studied the actions of positive and negative allosteric modulators within the transmembrane domain of mGluR5 , using enhance-sampling all-atom molecular dynamics simulations. We found dual binding modes of the PAM, associated with distinct shapes of the allosteric pocket. The negative allosteric modulators, in contrast, showed only one binding mode. The simulations revealed the mechanism by which the PAM activated the receptor, in the absence of the orthosteric agonist (the so-called allosteric agonism). The mechanism relied on dynamic communications between amino-acid motifs that are highly conserved across class C GPCRs. The findings may guide structure-based design and virtual screening of allosteric modulators for mGluR5 as well as for other class C GPCRs.- Published
- 2019
- Full Text
- View/download PDF
3. Conserved Residues Control the T1R3-Specific Allosteric Signaling Pathway of the Mammalian Sweet-Taste Receptor.
- Author
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Chéron JB, Soohoo A, Wang Y, Golebiowski J, Antonczak S, Jiang P, and Fiorucci S
- Subjects
- Cells, Cultured, Cyclamates chemistry, Cyclamates pharmacology, HEK293 Cells, Humans, Ligands, Molecular Dynamics Simulation, Mutagenesis, Site-Directed, Receptors, G-Protein-Coupled chemistry, Receptors, G-Protein-Coupled metabolism, Allosteric Regulation genetics, Receptors, G-Protein-Coupled genetics, Signal Transduction genetics
- Abstract
Mammalian sensory systems detect sweet taste through the activation of a single heteromeric T1R2/T1R3 receptor belonging to class C G-protein-coupled receptors. Allosteric ligands are known to interact within the transmembrane domain, yet a complete view of receptor activation remains elusive. By combining site-directed mutagenesis with computational modeling, we investigate the structure and dynamics of the allosteric binding pocket of the T1R3 sweet-taste receptor in its apo form, and in the presence of an allosteric ligand, cyclamate. A novel positively charged residue at the extracellular loop 2 is shown to interact with the ligand. Molecular dynamics simulations capture significant differences in the behavior of a network of conserved residues with and without cyclamate, although they do not directly interact with the allosteric ligand. Structural models show that they adopt alternate conformations, associated with a conformational change in the transmembrane region. Site-directed mutagenesis confirms that these residues are unequivocally involved in the receptor function and the allosteric signaling mechanism of the sweet-taste receptor. Similar to a large portion of the transmembrane domain, they are highly conserved among mammals, suggesting an activation mechanism that is evolutionarily conserved. This work provides a structural basis for describing the dynamics of the receptor, and for the rational design of new sweet-taste modulators., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
- Published
- 2019
- Full Text
- View/download PDF
4. Zebrafish olfactory receptors ORAs differentially detect bile acids and bile salts.
- Author
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Cong X, Zheng Q, Ren W, Chéron JB, Fiorucci S, Wen T, Zhang C, Yu H, Golebiowski J, and Yu Y
- Subjects
- Amino Acid Sequence, Animals, Computer Simulation, Ligands, Mutagenesis, Site-Directed, Receptors, Odorant chemistry, Receptors, Odorant genetics, Structure-Activity Relationship, Zebrafish, Zebrafish Proteins chemistry, Zebrafish Proteins genetics, Bile Acids and Salts metabolism, Receptors, Odorant metabolism, Zebrafish Proteins metabolism
- Abstract
The fish olfactory receptor ORA family is orthologous to the mammalian vomeronasal receptors type 1. It consists of six highly conserved chemosensory receptors expected to be essential for survival and communication. We deorphanized the zebrafish ORA family in a heterologous cell system. The six receptors responded specifically to lithocholic acid (LCA) and closely related C
24 5β-bile acids/salts. LCA attracted zebrafish as strongly as food in behavioral tests, whereas the less potent cholanic acid elicited weaker attraction, consistent with the in vitro results. The ORA-ligand recognition patterns were probed with site-directed mutagenesis guided by in silico modeling. We revealed the receptors' structure-function relationship underlying their specificity and selectivity for these compounds. Bile acids/salts are putative fish semiochemicals or pheromones sensed by the olfactory system with high specificity. This work identified their receptors and provided the basis for probing the roles of ORAs and bile acids/salts in fish chemosensation., (© 2019 Cong et al.)- Published
- 2019
- Full Text
- View/download PDF
5. Exploring the potential of a structural alphabet-based tool for mining multiple target conformations and target flexibility insight.
- Author
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Regad L, Chéron JB, Triki D, Senac C, Flatters D, and Camproux AC
- Subjects
- Animals, Catalytic Domain, HIV Protease chemistry, HIV Protease metabolism, Humans, Plasminogen Activators chemistry, Plasminogen Activators metabolism, Protein Binding, Protein Conformation, Tumor Suppressor Protein p53 chemistry, Tumor Suppressor Protein p53 metabolism, Sequence Analysis, Protein methods, Software
- Abstract
Protein flexibility is often implied in binding with different partners and is essential for protein function. The growing number of macromolecular structures in the Protein Data Bank entries and their redundancy has become a major source of structural knowledge of the protein universe. The analysis of structural variability through available redundant structures of a target, called multiple target conformations (MTC), obtained using experimental or modeling methods and under different biological conditions or different sources is one way to explore protein flexibility. This analysis is essential to improve the understanding of various mechanisms associated with protein target function and flexibility. In this study, we explored structural variability of three biological targets by analyzing different MTC sets associated with these targets. To facilitate the study of these MTC sets, we have developed an efficient tool, SA-conf, dedicated to capturing and linking the amino acid and local structure variability and analyzing the target structural variability space. The advantage of SA-conf is that it could be applied to divers sets composed of MTCs available in the PDB obtained using NMR and crystallography or homology models. This tool could also be applied to analyze MTC sets obtained by dynamics approaches. Our results showed that SA-conf tool is effective to quantify the structural variability of a MTC set and to localize the structural variable positions and regions of the target. By selecting adapted MTC subsets and comparing their variability detected by SA-conf, we highlighted different sources of target flexibility such as induced by binding partner, by mutation and intrinsic flexibility. Our results support the interest to mine available structures associated with a target using to offer valuable insight into target flexibility and interaction mechanisms. The SA-conf executable script, with a set of pre-compiled binaries are available at http://www.mti.univ-paris-diderot.fr/recherche/plateformes/logiciels.
- Published
- 2017
- Full Text
- View/download PDF
6. Update of the ATTRACT force field for the prediction of protein-protein binding affinity.
- Author
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Chéron JB, Zacharias M, Antonczak S, and Fiorucci S
- Subjects
- Databases, Protein, Protein Binding, Molecular Docking Simulation, Proteins chemistry, Thermodynamics
- Abstract
Determining the protein-protein interactions is still a major challenge for molecular biology. Docking protocols has come of age in predicting the structure of macromolecular complexes. However, they still lack accuracy to estimate the binding affinities, the thermodynamic quantity that drives the formation of a complex. Here, an updated version of the protein-protein ATTRACT force field aiming at predicting experimental binding affinities is reported. It has been designed on a dataset of 218 protein-protein complexes. The correlation between the experimental and predicted affinities reaches 0.6, outperforming most of the available protocols. Focusing on a subset of rigid and flexible complexes, the performance raises to 0.76 and 0.69, respectively. © 2017 Wiley Periodicals, Inc., (© 2017 Wiley Periodicals, Inc.)
- Published
- 2017
- Full Text
- View/download PDF
7. Sweetness prediction of natural compounds.
- Author
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Chéron JB, Casciuc I, Golebiowski J, Antonczak S, and Fiorucci S
- Subjects
- Biological Products, Humans, Structure-Activity Relationship, Sweetening Agents chemistry
- Abstract
Based on the most exhaustive database of sweeteners with known sweetness values, a new quantitative structure-activity relationship model for sweetness prediction has been set up. Analysis of the physico-chemical properties of sweeteners in the database indicates that the structure of most potent sweeteners combines a hydrophobic scaffold functionalized by a limited number of hydrogen bond sites (less than 4 hydrogen bond donors and 10 acceptors), with a moderate molecular weight ranging from 350 to 450g·mol
-1 . Prediction of sweetness, bitterness and toxicity properties of the largest database of natural compounds have been performed. In silico screening reveals that the majority of the predicted natural intense sweeteners comprise saponin or stevioside scaffolds. The model highlights that their sweetness potency is comparable to known natural sweeteners. The identified compounds provide a rational basis to initiate the design and chemosensory analysis of new low-calorie sweeteners., (Copyright © 2016 Elsevier Ltd. All rights reserved.)- Published
- 2017
- Full Text
- View/download PDF
8. The anatomy of mammalian sweet taste receptors.
- Author
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Chéron JB, Golebiowski J, Antonczak S, and Fiorucci S
- Subjects
- Amino Acid Sequence, Binding Sites, Gene Expression, Humans, Ligands, Models, Molecular, Point Mutation, Protein Binding, Protein Interaction Domains and Motifs, Protein Multimerization, Protein Structure, Secondary, Receptor, Metabotropic Glutamate 5 genetics, Receptors, G-Protein-Coupled genetics, Receptors, Metabotropic Glutamate genetics, Sequence Alignment, Structural Homology, Protein, Taste physiology, Receptor, Metabotropic Glutamate 5 chemistry, Receptors, G-Protein-Coupled chemistry, Receptors, Metabotropic Glutamate chemistry, Sweetening Agents chemistry
- Abstract
All sweet-tasting compounds are detected by a single G-protein coupled receptor (GPCR), the heterodimer T1R2-T1R3, for which no experimental structure is available. The sweet taste receptor is a class C GPCR, and the recently published crystallographic structures of metabotropic glutamate receptor (mGluR) 1 and 5 provide a significant step forward for understanding structure-function relationships within this family. In this article, we recapitulate more than 600 single point site-directed mutations and available structural data to obtain a critical alignment of the sweet taste receptor sequences with respect to other class C GPCRs. Using this alignment, a homology 3D-model of the human sweet taste receptor is built and analyzed to dissect out the role of key residues involved in ligand binding and those responsible for receptor activation. Proteins 2017; 85:332-341. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)
- Published
- 2017
- Full Text
- View/download PDF
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