Structural basis of odorant recognition by a human odorant receptor

• DOI: 10.1101/2022.12.20.520951
• Publication Date: 2022-12-21T01:35:27Z
• Authors: Christian B. Bill...; Claire A. de March; Wijnand J. C. van...; Ning Ma; Jeevan Tewari; Claudia Llinas de...; Linus Li; Bryan Faust; Nagarajan Vaidehi; Hiroaki Matsunami; Aashish Manglik
• Keywords: 0301 basic medicine; Binding Sites; Cryoelectron Microscopy; Molecular Dynamics Simulation; Receptors, Odorant; Substrate Specificity; Smell; 03 medical and health sciences; Odorant; Receptors; Odorants; Mutation; Humans; Propionates

Abstract Our sense of smell enables us to navigate a vast space chemically diverse odor molecules. This task is accomplished by the combinatorial activation approximately 400 olfactory G protein-coupled receptors (GPCRs) encoded in human genome 1–3 . How odorants are recognized (ORs) remains mysterious. Here we provide mechanistic insight into how an odorant binds receptor. Using cryogenic electron microscopy (cryo-EM), determined structure active OR51E2 bound fatty acid propionate. Propionate within occluded pocket and makes specific contacts critical receptor activation. Mutation binding alters recognition spectrum for acids varying chain length, suggesting that selectivity controlled tight packing interactions between Molecular dynamics simulations demonstrate propionate-induced conformational changes extracellular loop 3 activate OR51E2. Together, our studies high-resolution view chemical vertebrate OR, providing this large family GPCRs sense.