Inaccurately perceived as niche drugs, antiemetics are key elements of cancer treatment alleviating the most dreaded side effect of chemotherapy. Serotonin 5-HT3 receptor antagonists are the most commonly prescribed class of drugs to control chemotherapy-induced nausea and vomiting. These antagonists have been clinically successful drugs since the 1980s, yet our understanding of how they operate at the molecular level has been hampered by the difficulty of obtaining structures of drug-receptor complexes. Here, we report the cryoelectron microscopy structure of the palonosetron-bound 5-HT3 receptor. We investigate the binding of palonosetron, granisetron, dolasetron, ondansetron, and cilansetron using molecular dynamics, covering the whole set of antagonists used in clinical practice. The structural and computational results yield detailed atomic insight into the binding modes of the drugs. In light of our data, we establish a comprehensive framework underlying the inhibition mechanism by the -setron drug family.

止吐药被错误地视为小众药物，是减轻化疗最可怕副作用的癌症治疗的关键要素。血清素 5-HT3 受体拮抗剂是最常用的一类药物，用于控制化疗引起的恶心和呕吐。自 1980 年代以来，这些拮抗剂一直是临床上成功的药物，但由于难以获得药物受体复合物的结构，我们对它们如何在分子水平上运作的理解受到了阻碍。在这里，我们报告了帕洛诺司琼结合的 5-HT3 受体的冷冻电子显微镜结构。我们使用分子动力学研究帕洛诺司琼、格拉司琼、多拉司琼、昂丹司琼和西兰司琼的结合，涵盖临床实践中使用的全套拮抗剂。结构和计算结果产生了对药物结合模式的详细原子洞察。根据我们的数据，我们建立了 β-setron 药物家族抑制机制的综合框架。