Structural basis of antagonist selectivity in endothelin receptors

Abstract

Abstract 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.