View source for 9jh5


==Activation mechanism of CYSLTR2 by C16:0 ceramide==
<StructureSection load='9jh5' size='340' side='right'caption='[[9jh5]], [[Resolution|resolution]] 2.76&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[9jh5]] is a 6 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens], [https://en.wikipedia.org/wiki/Lama_glama Lama glama] and [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=9JH5 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9JH5 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]] 2.76&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=16C:N-((E,2S,3R)-1,3-DIHYDROXYOCTADEC-4-EN-2-YL)PALMITAMIDE'>16C</scene>, <scene name='pdbligand=CLR:CHOLESTEROL'>CLR</scene></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=9jh5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9jh5 OCA], [https://pdbe.org/9jh5 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9jh5 RCSB], [https://www.ebi.ac.uk/pdbsum/9jh5 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9jh5 ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/CLTR2_HUMAN CLTR2_HUMAN] Uveal melanoma. 
== Function ==
[https://www.uniprot.org/uniprot/CLTR2_HUMAN CLTR2_HUMAN] Receptor for cysteinyl leukotrienes. The response is mediated via a G-protein that activates a phosphatidylinositol-calcium second messenger system. Stimulation by BAY u9773, a partial agonist, induces specific contractions of pulmonary veins and might also have an indirect role in the relaxation of the pulmonary vascular endothelium. The rank order of affinities for the leukotrienes is LTC4 = LTD4 >> LTE4.
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== Publication Abstract from PubMed ==
Recent evidence has shown that increased levels of circulating long-chain ceramides predict atherosclerotic cardiovascular disease independently of cholesterol(1,2). Although targeting ceramide signalling may provide therapeutic benefits beyond the treatment of hypercholesterolaemia, the underlying mechanism by which circulating ceramides aggravate atherosclerotic cardiovascular disease remains elusive. Here we examine whether circulating long-chain ceramides activate membrane G-protein-coupled receptors to exacerbate atherosclerosis. We perform a systematic screen that combines G-protein-signalling quantification, bioinformatic analysis of G-protein-coupled receptor expression and functional examination of NLRP3 inflammasome activation. The results suggest that CYSLTR2 and P2RY6 are potential endogenous receptors of C16:0 ceramide-induced inflammasome activation in both endothelial cells and macrophages. Inhibition of CYSLTR2 and P2RY6 genetically or pharmacologically alleviates ceramide-induced atherosclerosis aggravation. Moreover, increased ceramide levels correlate with the severity of coronary artery disease in patients with varying degrees of renal impairment. Notably, CYSLTR2 and P2RY6 deficiency mitigates chronic-kidney-disease-aggravated atherosclerosis in mice without affecting cholesterol or ceramide levels. Structural analyses of ceramide-CYSLTR2-G(q) complexes reveal that both C16:0 and C20:0 ceramides bind in an inclined channel-like ligand-binding pocket on CYSLTR2. We further reveal an unconventional mechanism underlying ceramide-induced CYSLTR2 activation and the CYSLTR2-G(q) interface. Overall, our study provides structural and molecular mechanisms of how long-chain ceramides initiate transmembrane G(q) and inflammasome signalling through direct binding to CYSLTR2 and P2RY6 receptors. Therefore, blocking these signals may provide a new therapeutic potential to treat atherosclerosis-related diseases.

Sensing ceramides by CYSLTR2 and P2RY6 to aggravate atherosclerosis.,Zhang S, Lin H, Wang J, Rui J, Wang T, Cai Z, Huang S, Gao Y, Ma T, Fan R, Dai R, Li Z, Jia Y, Chen Q, He H, Tan J, Zhu S, Gu R, Dong Z, Li M, Xie E, Fu Y, Zheng J, Jiang C, Sun J, Kong W Nature. 2025 Mar 6. doi: 10.1038/s41586-025-08792-8. PMID:40049228<ref>PMID:40049228</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 9jh5" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Lama glama]]
[[Category: Large Structures]]
[[Category: Mus musculus]]
[[Category: Ding JH]]
[[Category: Sun JP]]
[[Category: Wang JL]]
[[Category: Yu X]]