Structural 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 complex with G_q, 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_A. Furthermore, our results suggest that ECL2 in ET_A 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.