Abstract
Olfactory systems must detect and discriminate amongst an enormous variety of odorants1. To contend with this challenge, diverse species have converged on a common strategy in which odorant identity is encoded through the combinatorial activation of large families of olfactory receptors1–3, thus allowing a finite number of receptors to detect a vast chemical world. Here we offer structural and mechanistic insight into how an individual olfactory receptor can flexibly recognize diverse odorants. We show that the olfactory receptor MhOR5 from the jumping bristletail4Machilis hrabei assembles as a homotetrameric odorant-gated ion channel with broad chemical tuning. Using cryo-electron microscopy, we elucidated the structure of MhOR5 in multiple gating states, alone and in complex with two of its agonists—the odorant eugenol and the insect repellent DEET. Both ligands are recognized through distributed hydrophobic interactions within the same geometrically simple binding pocket located in the transmembrane region of each subunit, suggesting a structural logic for the promiscuous chemical sensitivity of this receptor. Mutation of individual residues lining the binding pocket predictably altered the sensitivity of MhOR5 to eugenol and DEET and broadly reconfigured the receptor’s tuning. Together, our data support a model in which diverse odorants share the same structural determinants for binding, shedding light on the molecular recognition mechanisms that ultimately endow the olfactory system with its immense discriminatory capacity.
Highlights
Mammals and insects rely on distinct molecular mechanisms for odour detection, they share a common neural logic for olfactory perception based on the combinatorial activation of distinct ensembles of olfactory receptors and associated sensory neurons[1,3,12]
Neopteran insects each express a repertoire of highly divergent ORs along with a single, almost invariant Orco[2], recent genomic analyses have revealed that some basal insects, such as the jumping bristletail M. hrabei, possess only a small number of OR genes and lack an apparent Orco orthologue[4] (Fig. 1a)
Given its sensitivity to a broad array of structurally diverse odorants, we focused on MhOR5 to investigate the molecular basis of promiscuous chemical recognition
Summary
Membrane and diverges into four lateral conduits formed at the interfaces between subunits (Fig. 2a, b). In the presence of eugenol, the extracellular aperture of the pore is dilated as a result of movement of the S7b helices away from the central pore axis (Fig. 2b–d), which rotates Val[468] out of the pore lumen to face the lipid bilayer, while Gln[467] rotates in to face the ion pathway. The dilation of the S7b helices appears to be sufficient to gate the ion conduction pathway—this small conformational change would present a low energetic barrier to gating, consistent with the low affinity of most odorants[11,17] and with functional evidence that MhOR5 channels, as with many insect olfactory receptors, open spontaneously even in the absence of ligand[7,11] (Extended Data Fig. 1c). Defined density consistent with the size and shape of eugenol
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