8xvh: Difference between revisions
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==Cryo-EM structure of ETBR bound with Endothelin1== | |||
<StructureSection load='8xvh' size='340' side='right'caption='[[8xvh]], [[Resolution|resolution]] 3.26Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[8xvh]] is a 6 chain structure with sequence from [https://en.wikipedia.org/wiki/Clostridium_perfringens Clostridium perfringens], [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Lama_glama Lama glama]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8XVH OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8XVH 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]] 3.26Å</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=8xvh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8xvh OCA], [https://pdbe.org/8xvh PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8xvh RCSB], [https://www.ebi.ac.uk/pdbsum/8xvh PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8xvh ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/EDN1_HUMAN EDN1_HUMAN] Endothelins are endothelium-derived vasoconstrictor peptides. | |||
<div style="background-color:#fffaf0;"> | |||
== 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®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
<div class="pdbe-citations 8xvh" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Clostridium perfringens]] | |||
[[Category: Homo sapiens]] | |||
[[Category: Lama glama]] | |||
[[Category: Large Structures]] | |||
[[Category: Hou JY]] | |||
[[Category: Hua T]] | |||
[[Category: Liu SH]] | |||
[[Category: Liu ZJ]] | |||
[[Category: Wu LJ]] | |||
Latest revision as of 08:25, 28 August 2024
Cryo-EM structure of ETBR bound with Endothelin1Cryo-EM structure of ETBR bound with Endothelin1
Structural highlights
FunctionEDN1_HUMAN Endothelins are endothelium-derived vasoconstrictor peptides. Publication Abstract from PubMedEndothelins 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[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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