Extracellular loop 2 of G protein-coupled olfactory receptors is critical for odorant recognition
| Autor: | Yiqun Yu, Jody Pacalon, Zhenjie Ma, Xiaojing Cong, Jérôme Golebiowski, Lun Xu, Christine Belloir, Loïc Briand, Jérémie Topin |
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| Přispěvatelé: | Julien, Sabine, Fudan University [Shanghai], University of Shanghai [Shanghai], Institut de Chimie de Nice (ICN), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Centre des Sciences du Goût et de l'Alimentation [Dijon] (CSGA), Université de Bourgogne (UB)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut Agro Dijon, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), Université Bourgogne Franche-Comté [COMUE] (UBFC), Institut de Génomique Fonctionnelle (IGF), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM) |
| Rok vydání: | 2021 |
| Předmět: |
Protein Conformation
alpha-Helical Odorant binding G protein [SDV]Life Sciences [q-bio] Mutagenesis (molecular biology technique) Molecular Dynamics Simulation Ligands Receptors Odorant Biochemistry Mice [SDV.BBM] Life Sciences [q-bio]/Biochemistry Molecular Biology Extracellular Olfactory receptor Animals Humans [SDV.BBM]Life Sciences [q-bio]/Biochemistry Molecular Biology Receptor Molecular Biology G protein-coupled receptor Virtual screening molecular modeling Chemistry Cell Biology virtual screening Ligand (biochemistry) Cell biology [SDV] Life Sciences [q-bio] Smell [SDV.AEN] Life Sciences [q-bio]/Food and Nutrition Odorants Mutagenesis Site-Directed site-directed mutagenesis [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition |
| Zdroj: | Journal of Biological Chemistry Journal of Biological Chemistry, 2022, 298 (9), pp.102331. ⟨10.1016/j.jbc.2022.102331⟩ |
| ISSN: | 0021-9258 1083-351X |
| Popis: | International audience; G protein-coupled olfactory receptors (ORs) enable us to detect innumerous odorants. They are also ectopically expressed in non-olfactory tissues and emerging as attractive drug targets. ORs can be promiscuous or highly specific, which is part of a larger mechanism for odor discrimination. Here, we demonstrate that the OR extracellular loop 2 (ECL2) plays critical roles in OR promiscuity and specificity. Using site-directed mutagenesis and molecular modeling, we constructed 3D OR models in which ECL2 forms a lid over the orthosteric pocket. We demonstrate using molecular dynamics simulations that ECL2 controls the shape and the volume of the odorant-binding pocket, maintains the pocket hydrophobicity, and acts as a gatekeeper of odorant binding. Therefore, we propose the interplay between the specific orthosteric pocket and the variable, less specific ECL2 controls OR specificity and promiscuity. Furthermore, the 3D models created here enabled virtual screening of new OR agonists and antagonists, which exhibited a 70% hit rate in cell assays. Our approach can potentially be generalized to structure-based ligand screening for other GPCRs that lack high-resolution 3D structures. |
| Databáze: | OpenAIRE |
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