8xvk

Cryo-EM structure of ETAR bound with Ambrisentan

spinqualitylabelsall models 8xvk, resolution 3.21Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8xvk is a 4 chain structure with sequence from Acetivibrio thermocellus ATCC 27405, Escherichia coli, Homo sapiens and Synthetic construct. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Electron Microscopy, Resolution 3.21Å Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease EDNRA_HUMAN Cystic fibrosis;Mandibulofacial dysostosis with alopecia. The disease is caused by variants affecting the gene represented in this entry. Function C562_ECOLX Electron-transport protein of unknown function.GUNH_ACET2 This enzyme catalyzes the endohydrolysis of 1,4-beta-glucosidic linkages in cellulose, lichenin and cereal beta-D-glucans.EDNRA_HUMAN Receptor for endothelin-1. Mediates its action by association with G proteins that activate a phosphatidylinositol-calcium second messenger system. The rank order of binding affinities for ET-A is: ET1 > ET2 >> ET3. Publication Abstract from PubMed 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. Structural basis of antagonist selectivity in endothelin receptors.,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 Cell Discov. 2024 Jul 30;10(1):79. doi: 10.1038/s41421-024-00705-9. PMID:39075075 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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