Structural basis of odorant recognition by a human odorant receptor
Résumé
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 lengths, 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.
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