{"title":"Structural basis of antagonist selectivity in endothelin receptors.","authors":"Junyi Hou, Shenhui Liu, Xiaodan Zhang, Guowei Tu, Lijie Wu, Yijie Zhang, Hao Yang, Xiangcheng Li, Junlin Liu, Longquan Jiang, Qiwen Tan, Fang Bai, Zhijie Liu, Changhong Miao, Tian Hua, Zhe Luo","doi":"10.1038/s41421-024-00705-9","DOIUrl":null,"url":null,"abstract":"<p><p>Endothelins and their receptors, ET<sub>A</sub> and ET<sub>B</sub>, play vital roles in maintaining vascular homeostasis. Therapeutically targeting endothelin receptors, particularly through ET<sub>A</sub> antagonists, has shown efficacy in treating pulmonary arterial hypertension (PAH) and other cardiovascular- and renal-related diseases. Here we present cryo-electron microscopy structures of ET<sub>A</sub> in complex with two PAH drugs, macitentan and ambrisentan, along with zibotentan, a selective ET<sub>A</sub> antagonist, respectively. Notably, a specialized anti-ET<sub>A</sub> antibody facilitated the structural elucidation. These structures, together with the active-state structures of ET-1-bound ET<sub>A</sub> and ET<sub>B</sub>, and the agonist BQ3020-bound ET<sub>B</sub>, in complex with G<sub>q</sub>, unveil the molecular basis of agonist/antagonist binding modes in endothelin receptors. Key residues that confer antagonist selectivity to endothelin receptors were identified along with the activation mechanism of ET<sub>A</sub>. Furthermore, our results suggest that ECL2 in ET<sub>A</sub> can serve as an epitope for antibody-mediated receptor antagonism. Collectively, these insights establish a robust theoretical framework for the rational design of small-molecule drugs and antibodies with selective activity against endothelin receptors.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":null,"pages":null},"PeriodicalIF":13.0000,"publicationDate":"2024-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11286772/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cell Discovery","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1038/s41421-024-00705-9","RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Endothelins and their receptors, ETA and ETB, play vital roles in maintaining vascular homeostasis. Therapeutically targeting endothelin receptors, particularly through ETA antagonists, has shown efficacy in treating pulmonary arterial hypertension (PAH) and other cardiovascular- and renal-related diseases. Here we present cryo-electron microscopy structures of ETA in complex with two PAH drugs, macitentan and ambrisentan, along with zibotentan, a selective ETA antagonist, respectively. Notably, a specialized anti-ETA antibody facilitated the structural elucidation. These structures, together with the active-state structures of ET-1-bound ETA and ETB, and the agonist BQ3020-bound ETB, in complex with Gq, unveil the molecular basis of agonist/antagonist binding modes in endothelin receptors. Key residues that confer antagonist selectivity to endothelin receptors were identified along with the activation mechanism of ETA. Furthermore, our results suggest that ECL2 in ETA can serve as an epitope for antibody-mediated receptor antagonism. Collectively, these insights establish a robust theoretical framework for the rational design of small-molecule drugs and antibodies with selective activity against endothelin receptors.
内皮素及其受体 ETA 和 ETB 在维持血管稳态方面发挥着重要作用。以内皮素受体为治疗靶点,特别是通过 ETA 拮抗剂,已显示出治疗肺动脉高压(PAH)和其他心血管及肾脏相关疾病的疗效。在这里,我们展示了 ETA 分别与两种 PAH 药物(马基坦坦和安利生坦)以及选择性 ETA 拮抗剂齐博坦复合物的冷冻电镜结构。值得注意的是,专门的抗 ETA 抗体促进了结构的阐明。这些结构,连同 ET-1 结合 ETA 和 ETB 的活性状态结构,以及激动剂 BQ3020 结合 ETB 与 Gq 复合物的结构,揭示了内皮素受体激动剂/拮抗剂结合模式的分子基础。我们确定了赋予内皮素受体拮抗剂选择性的关键残基以及 ETA 的激活机制。此外,我们的研究结果表明,ETA 中的 ECL2 可作为抗体介导的受体拮抗作用的表位。总之,这些见解为合理设计对内皮素受体具有选择性活性的小分子药物和抗体建立了坚实的理论框架。
Cell DiscoveryBiochemistry, Genetics and Molecular Biology-Molecular Biology
CiteScore
24.20
自引率
0.60%
发文量
120
审稿时长
20 weeks
期刊介绍:
Cell Discovery is a cutting-edge, open access journal published by Springer Nature in collaboration with the Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences (CAS). Our aim is to provide a dynamic and accessible platform for scientists to showcase their exceptional original research.
Cell Discovery covers a wide range of topics within the fields of molecular and cell biology. We eagerly publish results of great significance and that are of broad interest to the scientific community. With an international authorship and a focus on basic life sciences, our journal is a valued member of Springer Nature's prestigious Molecular Cell Biology journals.
In summary, Cell Discovery offers a fresh approach to scholarly publishing, enabling scientists from around the world to share their exceptional findings in molecular and cell biology.