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 receptors^1,2,3, 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 bristletail⁴ Machilis 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.

嗅觉系统必须检测并区分种类繁多的气味¹ 。为了应对这一挑战，不同的物种已经集中在一个共同的策略上，即通过嗅觉受体大家族的组合激活来编码气味特性^1,2,3 ，从而允许有限数量的受体检测广阔的化学世界。在这里，我们提供了关于单个嗅觉受体如何灵活识别不同气味的结构和机制的见解。我们证明，来自跳跃鬃尾⁴ Machilis hrabei 的嗅觉受体Mh OR5 组装成具有广泛化学调节的同源四聚体气味门控离子通道。使用冷冻电子显微镜，我们阐明了Mh OR5 在多种门控状态下的结构，包括单独的结构和与其两种激动剂（气味剂丁子香酚和驱虫剂避蚊胺）的复合物。两种配体通过位于每个亚基跨膜区域的相同几何简单结合袋内的分布式疏水相互作用来识别，这表明该受体的混杂化学敏感性的结构逻辑。结合口袋内衬的单个残基的突变可预测地改变了Mh OR5 对丁子香酚和避蚊胺的敏感性，并广泛地重新配置了受体的调节。总之，我们的数据支持了一个模型，其中不同的气味剂具有相同的结合结构决定因素，揭示了分子识别机制，最终赋予嗅觉系统巨大的辨别能力。