Basak Sandip, Kumar Arvind, Ramsey Steven, Gibbs Eric, Kapoor Abhijeet, Filizola Marta, Chakrapani Sudha
Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, United States.
Cleveland Center for Membrane and Structural Biology, Case Western Reserve University, Cleveland, United States.
Elife. 2020 Oct 16;9:e57870. doi: 10.7554/eLife.57870.
Serotonin receptors (5-HTR) play a crucial role in regulating gut movement, and are the principal target of setrons, a class of high-affinity competitive antagonists, used in the management of nausea and vomiting associated with radiation and chemotherapies. Structural insights into setron-binding poses and their inhibitory mechanisms are just beginning to emerge. Here, we present high-resolution cryo-EM structures of full-length 5-HTR in complex with palonosetron, ondansetron, and alosetron. Molecular dynamic simulations of these structures embedded in a fully-hydrated lipid environment assessed the stability of ligand-binding poses and drug-target interactions over time. Together with simulation results of apo- and serotonin-bound 5-HTR, the study reveals a distinct interaction fingerprint between the various setrons and binding-pocket residues that may underlie their diverse affinities. In addition, varying degrees of conformational change in the setron-5-HTR structures, throughout the channel and particularly along the channel activation pathway, suggests a novel mechanism of competitive inhibition.
血清素受体（5 - HTR）在调节肠道运动中起关键作用，并且是一类高亲和力竞争性拮抗剂——5 - 羟色胺类药物（setrons）的主要作用靶点，这类药物用于治疗与放疗和化疗相关的恶心和呕吐。关于5 - 羟色胺类药物结合姿态及其抑制机制的结构见解才刚刚开始出现。在此，我们展示了全长5 - HTR与帕洛诺司琼、昂丹司琼和阿洛司琼复合物的高分辨率冷冻电镜结构。对嵌入完全水合脂质环境中的这些结构进行分子动力学模拟，评估了配体结合姿态和药物 - 靶点相互作用随时间的稳定性。结合无配体和血清素结合的5 - HTR的模拟结果，该研究揭示了各种5 - 羟色胺类药物与结合口袋残基之间独特的相互作用特征，这可能是它们不同亲和力的基础。此外，5 - 羟色胺类药物 - 5 - HTR结构在整个通道，特别是沿通道激活途径存在不同程度的构象变化，提示了一种新的竞争性抑制机制。
