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Odorant Receptor 7D4 Activation Dynamics

Title
Odorant Receptor 7D4 Activation Dynamics
Authors
deMarch, C.A.Topin, J.Bruguera, E.Novikov, G.Ikegami, K.Matsunami, H.Golebiowski, Jerome
Issue Date
2018-04
Citation
Angewandte Chemie - International Edition, 57(17), 4554-4558
Type
Article
Article Type
Article
Keywords
BiochemistryMolecular dynamicsMolecular modelingOdorsProteinsActivation mechanismsComputational modelFunctional assaysG protein coupled receptorsGenetic polymorphismsMolecular simulationsOlfactory receptorsSite directed mutagenesisChemical activation
ISSN
1433-7851
Abstract
Deciphering how an odorant activates an odorant receptor (OR) and how changes in specific OR residues affect its responsiveness are central to understanding our sense of smell. A joint approach combining site-directed mutagenesis and functional assays with computational modeling has been used to explore the signaling mechanics of OR7D4. In this OR, a genetic polymorphism affects our perception of androstenone. Molecular simulations totaling 0.12ms predicted that, similarly to observations for other G-protein-coupled receptors with known experimental structures, an activation pathway connects the ligand and the G-protein binding site. The 3D model activation mechanism correlates with in vitro data and notably predicts that the OR7D4 WM variant is not activated. Upon activation, an OR-specific sequence motif is the convergence point of the mechanism. Our study suggests that robust homology modeling can serve as a powerful tool to capture OR dynamics related to smell perception. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.
URI
http://hdl.handle.net/20.500.11750/6209
DOI
10.1002/anie.201713065
Publisher
Wiley-VCH Verlag
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