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Structural basis of antagonist selectivity in endothelin receptors.
Hou, Junyi; Liu, Shenhui; Zhang, Xiaodan; Tu, Guowei; Wu, Lijie; Zhang, Yijie; Yang, Hao; Li, Xiangcheng; Liu, Junlin; Jiang, Longquan; Tan, Qiwen; Bai, Fang; Liu, Zhijie; Miao, Changhong; Hua, Tian; Luo, Zhe.
Afiliación
  • Hou J; Cardiac Intensive Care Center, Zhongshan Hospital, Fudan University, Shanghai, China.
  • Liu S; iHuman Institute, ShanghaiTech University, Shanghai, China.
  • Zhang X; School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
  • Tu G; iHuman Institute, ShanghaiTech University, Shanghai, China.
  • Wu L; School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
  • Zhang Y; Cardiac Intensive Care Center, Zhongshan Hospital, Fudan University, Shanghai, China.
  • Yang H; iHuman Institute, ShanghaiTech University, Shanghai, China.
  • Li X; Cardiac Intensive Care Center, Zhongshan Hospital, Fudan University, Shanghai, China.
  • Liu J; School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
  • Jiang L; Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai, China.
  • Tan Q; School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
  • Bai F; Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai, China.
  • Liu Z; iHuman Institute, ShanghaiTech University, Shanghai, China.
  • Miao C; iHuman Institute, ShanghaiTech University, Shanghai, China.
  • Hua T; School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
  • Luo Z; iHuman Institute, ShanghaiTech University, Shanghai, China.
Cell Discov ; 10(1): 79, 2024 Jul 30.
Article en En | MEDLINE | ID: mdl-39075075
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Cell Discov Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Reino Unido
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Cell Discov Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Reino Unido