Conformational Sensing by a Mammalian Olfactory Receptor

Abstract

To identify odors, the mammalian nose deploys hundreds of olfactory receptors (ORs) from the rhodopsin‐like class of the G protein‐coupled receptor superfamily. Odorants having multiple rotatable bonds present a problem for the stereochemical shape‐based matching process assumed to govern the sense of smell through OR–odorant recognition. We conformationally restricted the carbon chain of the odorant octanal to ask whether an OR can respond differently to different odorant conformations. By using calcium imaging to monitor signal transduction in sensory neurons expressing the mouse aldehyde OR, Olfr2, we found that the spatial position of the C7 and C8 carbon atoms of octanal, in relation to its −CHO group, determines whether an aliphatic aldehyde functions as an agonist, partial agonist or antagonist. Our experiments provide evidence that an odorant can manipulate an OR through its intrinsic conformational repertoire, in unexpected analogy to the photon‐controlled aldehyde manipulation observed in rhodopsin.

A physicochemical model of odor sampling

“…To wit, it cannot be used to model the decomposition of odor mixtures [ 27 ], nor to strongly predict the activity of bulbar principal neurons [ 28 ], nor to study how the same physicochemical odorscene may be differently sampled by the noses of different animal species (potentially resulting in different patterns of similarity within their respective R-spaces). Moreover, the use of molecular descriptors is less concrete than it may initially seem, as the aggregate physical properties of the whole molecule gloss over the intramolecular heterogeneities such as localized charge distributions that directly influence ligand-receptor interactions (notably, single odorant molecules present multiple prospective binding sites to different receptors, the conformation of which is critical; [ 29 ]). The strength of such approaches, of course, is that they are based on the responses to actual odorants rather than to theoretical odorant constructs, and they can offer some predictive utility within localized regions of odor space.…”

A physicochemical model of odor sampling

“…To wit, it cannot be used to model the decomposition of odor mixtures [27], nor to strongly predict the activity of bulbar principal neurons [28], nor to study how the same physicochemical odorscene may be differently sampled by the noses of different animal species (potentially resulting in different patterns of similarity within their respective Rspaces). Moreover, the use of molecular descriptors is less concrete than it may initially seem, as the aggregate physical properties of the whole molecule gloss over the intramolecular heterogeneities such as localized charge distributions that directly influence ligand-receptor interactions (notably, single odorant molecules present multiple prospective binding sites to different receptors, the conformation of which is critical; [29]). The strength of such approaches, of course, is that they are based on the responses to actual odorants rather than to theoretical odorant constructs, and they can offer some predictive utility within localized regions of odor space.…”