美国加州大学旧金山分校Aashish Manglik等研究人员合作揭示人类气味受体识别气味的结构基础。相关论文于2023年3月15日在线发表在《自然》杂志上。

研究人员对气味剂如何与人类气味受体结合提供了机械性的见解。利用冷冻电镜，研究人员确定了活性人类气味受体OR51E2与脂肪酸丙酸盐结合的结构。丙酸盐在OR51E2的一个封闭口袋中结合，并与受体激活有关键的特定接触。OR51E2中气味结合口袋的突变改变了对不同链长脂肪酸的识别光谱，这表明气味的选择性是由气味剂和气味受体之间的紧密包装相互作用控制的。分子动力学模拟表明，丙酸盐诱导的细胞外环3的构象变化激活了OR51E2。总之，这项研究提供了一个脊椎动物气味受体对气味剂化学识别的高分辨率视图，并提供了对这个大的G蛋白偶联受体家族如何实现人类嗅觉的深入了解。

据了解，人类嗅觉使之能够在化学性质不同的气味分子的广阔空间中导航。这项任务是通过人类基因组中编码的大约400个气味G蛋白偶联受体的组合激活而完成的。气味受体是如何识别气味的仍不清楚。

附：英文原文

Title: Structural basis of odorant recognition by a human odorant receptor

Author: Billesblle, Christian B., de March, Claire A., van der Velden, Wijnand J. C., Ma, Ning, Tewari, Jeevan, del Torrent, Claudia Llinas, Li, Linus, Faust, Bryan, Vaidehi, Nagarajan, Matsunami, Hiroaki, Manglik, Aashish

Issue&Volume: 2023-03-15

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 genome1,2,3. 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.

DOI: 10.1038/s41586-023-05798-y

Source: https://www.nature.com/articles/s41586-023-05798-y