Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, OH, 44106-4970, USA.
Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Nat Commun. 2019 Jul 19;10(1):3225. doi: 10.1038/s41467-019-11142-8.
Serotonin receptor (5-HTR) is the most common therapeutic target to manage the nausea and vomiting during cancer therapies and in the treatment of irritable bowel syndrome. Setrons, a class of competitive antagonists, cause functional inhibition of 5-HTR in the gastrointestinal tract and brainstem, acting as effective anti-emetic agents. Despite their prevalent use, the molecular mechanisms underlying setron binding and inhibition of 5-HTR are not fully understood. Here, we present the structure of granisetron-bound full-length 5-HTR solved by single-particle cryo-electron microscopy to 2.92 Å resolution. The reconstruction reveals the orientation of granisetron in the orthosteric site with unambiguous density for interacting sidechains. Molecular dynamics simulations and electrophysiology confirm the granisetron binding orientation and the residues central for ligand recognition. Comparison of granisetron-bound 5-HTR with the apo and serotonin-bound structures, reveals key insights into the mechanism underlying 5-HTR inhibition.
血清素受体 (5-HTR) 是管理癌症治疗期间和治疗肠易激综合征时恶心和呕吐的最常见治疗靶点。选择性 5-羟色胺再摄取抑制剂 (setrons) 是竞争性拮抗剂的一类，可在胃肠道和脑干中引起 5-HTR 的功能抑制，作为有效的止吐剂。尽管它们被广泛使用，但 setron 结合和抑制 5-HTR 的分子机制尚未完全了解。在这里，我们通过单颗粒冷冻电子显微镜以 2.92 Å 的分辨率解决了 granisetron 结合全长 5-HTR 的结构。该重建揭示了 granisetron 在正位点的取向，具有与相互作用侧链的明确密度。分子动力学模拟和电生理学证实了 granisetron 的结合取向和对配体识别起核心作用的残基。与 apo 和 5-羟色胺结合结构的比较，揭示了 5-HTR 抑制机制的关键见解。
