View source for 8xvj


==Cryo-EM structure of ETAR bound with Macitentan==
<StructureSection load='8xvj' size='340' side='right'caption='[[8xvj]], [[Resolution|resolution]] 3.26&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8xvj]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Acetivibrio_thermocellus_ATCC_27405 Acetivibrio thermocellus ATCC 27405], [https://en.wikipedia.org/wiki/Escherichia_coli Escherichia coli], [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Synthetic_construct Synthetic construct]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8XVJ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8XVJ FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 3.26&#8491;</td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=8xvj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8xvj OCA], [https://pdbe.org/8xvj PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8xvj RCSB], [https://www.ebi.ac.uk/pdbsum/8xvj PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8xvj ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/EDNRA_HUMAN EDNRA_HUMAN] Mandibulofacial dysostosis with alopecia;Cystic fibrosis. The disease is caused by variants affecting the gene represented in this entry.
== Function ==
[https://www.uniprot.org/uniprot/C562_ECOLX C562_ECOLX] Electron-transport protein of unknown function.[https://www.uniprot.org/uniprot/EDNRA_HUMAN 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.[https://www.uniprot.org/uniprot/GUNH_ACET2 GUNH_ACET2] This enzyme catalyzes the endohydrolysis of 1,4-beta-glucosidic linkages in cellulose, lichenin and cereal beta-D-glucans.
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== 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<ref>PMID:39075075</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 8xvj" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Acetivibrio thermocellus ATCC 27405]]
[[Category: Escherichia coli]]
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Synthetic construct]]
[[Category: Hou JY]]
[[Category: Hua T]]
[[Category: Liu SH]]
[[Category: Liu ZJ]]
[[Category: Wu LJ]]