biostudies-literatureUnknown10(1)Hou JEndothelins and their receptors, ET_A and ET_B, play vital roles in maintaining vascular homeostasis. Therapeutically targeting endothelin receptors, particularly through ET_A 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_A in complex with two PAH drugs, macitentan and ambrisentan, along with zibotentan, a selective ET_A antagonist, respectively. Notably, a specialized anti-ET_A antibody facilitated the structural elucidation. These structures, together with the active-state structures of ET-1-bound ET_A and ET_B, and the agonist BQ3020-bound ET_B, in compCell discovery79https://www.ebi.ac.uk/biostudies/studies/S-EPMC11286772biostudies-literatureStructural basis of antagonist selectivity in endothelin receptors.PMC11286772Yang HLiu JWu LJiang LHua TLuo ZLiu STu GLi XHou JLiu ZZhang YZhang XMiao CTan QBai FfalseStructural basis of antagonist selectivity in endothelin receptors.Endothelins and their receptors, ET_A and ET_B, play vital roles in maintaining vascular homeostasis. Therapeutically targeting endothelin receptors, particularly through ET_A 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_A in complex with two PAH drugs, macitentan and ambrisentan, along with zibotentan, a selective ET_A antagonist, respectively. Notably, a specialized anti-ET_A antibody facilitated the structural elucidation. These structures, together with the active-state structures of ET-1-bound ET_A and ET_B, and the agonist BQ3020-bound ET_B, in comp2024-01-01T00:00:00Z2024 Jul2026-06-02T09:19:39.884Z2026-04-16T03:13:18.084ZS-EPMC112867723907507510.1038/s41421-024-00705-9