High-resolution structures of multiple 5-HT(3A)R-setron complexes reveal a novel mechanism of competitive inhibition.
High-resolution structures of multiple 5-HT(3A)R-setron complexes reveal a novel mechanism of competitive inhibition.
复制标题
多个5-HT（3A）R-Setron复合物的高分辨率结构揭示了一种新型的竞争抑制机制。
DOI：
10.7554/elife.57870
复制
发表时间：
2020-10-16
期刊：
影响因子：
7.7
通讯作者：
Chakrapani S
中科院分区：
文献类型：
--
作者：
Basak S;Kumar A;Ramsey S;Gibbs E;Kapoor A;Filizola M;Chakrapani S
5-羟色胺受体（5-HT3AR）在调节肠道运动中起着至关重要的作用，并且是setrons的主要靶点，setrons是一类高亲和力竞争拮抗剂，用于治疗放疗和化疗相关的恶心和呕吐。对setron结合姿势及其抑制机制的结构见解才刚刚开始出现。在这里，我们展示了全长5-HT3AR与帕洛诺司琼、昂丹司琼和阿洛司琼配合物的高分辨率低温电镜结构。这些结构嵌入在完全水合脂质环境中的分子动力学模拟评估了配体结合姿势和药物靶标相互作用随时间的稳定性。结合载子和血清素结合的5-HT3AR的模拟结果，该研究揭示了不同setrons和结合袋残基之间独特的相互作用指纹，这可能是它们不同亲和力的基础。此外，setron-5-HT3AR结构的不同程度的构象变化，贯穿整个通道，特别是沿着通道激活途径，表明了一种新的竞争性抑制机制。血清素可能是大脑中最著名的化学信使，它调节情绪、食欲和睡眠。但作为一种激素，血清素在身体的其他部位也起作用。血清素主要在肠道中产生，它与受体蛋白结合，帮助调节物质通过胃肠道的运动，帮助消化。然而，肠道中血清素释放的激增会引起呕吐和恶心，这通常是用放疗和化疗治疗癌症的副作用。因此，用于控制和预防癌症患者所经历的严重恶心和呕吐的抗恶心药物是针对肠道中的血清素受体设计的。这些被称为setrons的药物，通过在5 -羟色胺之前与5 -羟色胺受体结合而起作用，基本上抵消了任何多余的5 -羟色胺的作用。虽然它们通常以相同的方式靶向血清素受体，但有些setrons比其他setrons更有效，可以提供更持久的缓解。明确每种药物如何与其靶受体相互作用可能有助于解释它们的不同效果。Basak等人使用一种称为冷冻电子显微镜的技术来检查三种常见的抗恶心药物（帕洛诺司琼、昂丹司琼和阿洛司琼）与一种5-羟色胺受体5-HT3AR之间的相互作用。实验表明，每种药物都改变了5-HT3AR的形状，从而不同程度地抑制了其活性。进一步的分析确定了所研究的三种司酮药物的独特的“相互作用指纹”，显示了每种药物结合的受体亚基。它们相互作用的模拟也表明，水分子在这一过程中起着至关重要的作用，暴露了受体表面药物附着的结合袋。这项工作提供了抗恶心药物和血清素受体之间相互作用的结构蓝图。这种结构可以指导新的和改进的治疗癌症治疗引起的恶心和呕吐的疗法的发展。
Serotonin receptors (5-HT3AR) 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-HT3AR 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-HT3AR, 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-HT3AR structures, throughout the channel and particularly along the channel activation pathway, suggests a novel mechanism of competitive inhibition. Serotonin is perhaps best known as a chemical messenger in the brain, where it regulates mood, appetite and sleep. But as a hormone, serotonin works in other parts of the body too. Serotonin is predominantly made in the gut, where it binds receptor proteins that help to regulate the movement of substances through the gastrointestinal tract, aiding digestion. However, a surge in serotonin release in the gut induces vomiting and nausea, which commonly happens as a side effect of treating cancer with radiotherapy and chemotherapy. Anti-nausea drugs used to manage and prevent the severe nausea and vomiting experienced by cancer patients are therefore designed to target serotonin receptors in the gut. These drugs, called setrons, work by binding to serotonin receptors before serotonin does, essentially neutralising the effect of any surplus serotonin. Although they generally target serotonin receptors in the same way, some setrons are more efficient than others and can provide longer lasting relief. Clarifying exactly how each drug interacts with its target receptor might help to explain their differential effects. Basak et al. used a technique called cryo-electron microscopy to examine the interactions between three common anti-nausea drugs (palonosetron, ondansetron and alosetron) and one type of serotonin receptor, 5-HT3AR. The experiments showed that each drug changed the shape of 5-HT3AR, thereby inhibiting its activity to varying degrees. Further analysis identified a distinct ‘interaction fingerprint’ for the three setron drugs studied, showing which of the receptors’ subunits each drug binds to. Simulations of their interactions also showed that water molecules play a crucial role in the process, exposing the binding pocket on the receptor’s surface where the drugs attach. This work provides a structural blueprint of the interactions between anti-nausea drugs and serotonin receptors. The structures could guide the development of new and improved therapies to treat nausea and vomiting brought on by cancer treatments.
DOI：
10.1085/jgp.200308885
发表时间：
2003-11
期刊：
The Journal of general physiology
影响因子：
--
作者：
Chakrapani S;Bailey TD;Auerbach A
通讯作者：
Auerbach A