8XVE

Cryo-EM structure of ETBR bound with BQ3020

8XVE の概要

• エントリーDOI: 10.2210/pdb8xve/pdb
• EMDBエントリー: 38702
• 分子名称: Isoform Gnas-2 of Guanine nucleotide-binding protein G(s) subunit alpha isoforms short, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2, ... (6 entities in total)
• 機能のキーワード: gpcr, complex, etb, bq3020, signaling protein
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 189518.46

構造登録者

Hou, J.Y.,Liu, S.H.,Wu, L.J.,Liu, Z.J.,Hua, T. (登録日: 2024-01-15, 公開日: 2024-08-28, 最終更新日: 2025-07-23)

主引用文献

Hou, J.,Liu, S.,Zhang, X.,Tu, G.,Wu, L.,Zhang, Y.,Yang, H.,Li, X.,Liu, J.,Jiang, L.,Tan, Q.,Bai, F.,Liu, Z.,Miao, C.,Hua, T.,Luo, Z.
Structural basis of antagonist selectivity in endothelin receptors.
Cell Discov, 10:79-79, 2024

PubMed Abstract: Endothelins and their receptors, ET and ET, play vital roles in maintaining vascular homeostasis. Therapeutically targeting endothelin receptors, particularly through ET 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 in complex with two PAH drugs, macitentan and ambrisentan, along with zibotentan, a selective ET antagonist, respectively. Notably, a specialized anti-ET antibody facilitated the structural elucidation. These structures, together with the active-state structures of ET-1-bound ET and ET, and the agonist BQ3020-bound ET, in complex with G, 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. Furthermore, our results suggest that ECL2 in ET 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.

PubMed: 39075075
DOI: 10.1038/s41421-024-00705-9

実験手法

ELECTRON MICROSCOPY (3 Å)