Structural basis of odorant recognition by a human odorant receptor

Christian B. Billesbølle, Claire A. March, Wijnand J. C. Velden, Ning Ma, Jeevan Tewari, Claudia Llinas Torrent, Linus Li, Bryan Faust, Nagarajan Vaidehi (), Hiroaki Matsunami () and Aashish Manglik ()
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Christian B. Billesbølle: University of California
Claire A. March: Duke University
Wijnand J. C. Velden: Beckman Research Institute of the City of Hope
Ning Ma: Beckman Research Institute of the City of Hope
Jeevan Tewari: Duke University
Claudia Llinas Torrent: University of California
Linus Li: University of California
Bryan Faust: University of California
Nagarajan Vaidehi: Beckman Research Institute of the City of Hope
Hiroaki Matsunami: Duke University
Aashish Manglik: University of California

Nature, 2023, vol. 615, issue 7953, 742-749

Abstract: Abstract Our sense of smell enables us to navigate a vast space of chemically diverse odour molecules. This task is accomplished by the combinatorial activation of approximately 400 odorant G protein-coupled receptors encoded in the human genome1–3. How odorants are recognized by odorant receptors remains unclear. Here we provide mechanistic insight into how an odorant binds to a human odorant receptor. Using cryo-electron microscopy, we determined the structure of the active human odorant receptor OR51E2 bound to the fatty acid propionate. Propionate is bound within an occluded pocket in OR51E2 and makes specific contacts critical to receptor activation. Mutation of the odorant-binding pocket in OR51E2 alters the recognition spectrum for fatty acids of varying chain length, suggesting that odorant selectivity is controlled by tight packing interactions between an odorant and an odorant receptor. Molecular dynamics simulations demonstrate that propionate-induced conformational changes in extracellular loop 3 activate OR51E2. Together, our studies provide a high-resolution view of chemical recognition of an odorant by a vertebrate odorant receptor, providing insight into how this large family of G protein-coupled receptors enables our olfactory sense.

Date: 2023
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DOI: 10.1038/s41586-023-05798-y

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