View source for 8uxh


==Structure of PKA phosphorylated human RyR2-R420W in the primed state in the presence of calcium==
<StructureSection load='8uxh' size='340' side='right'caption='[[8uxh]], [[Resolution|resolution]] 3.52&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8uxh]] is a 8 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8UXH OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8UXH 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]] 3.52&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ATP:ADENOSINE-5-TRIPHOSPHATE'>ATP</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</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=8uxh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8uxh OCA], [https://pdbe.org/8uxh PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8uxh RCSB], [https://www.ebi.ac.uk/pdbsum/8uxh PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8uxh ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/RYR2_HUMAN RYR2_HUMAN] Familial isolated arrhythmogenic ventricular dysplasia, right dominant form;Catecholaminergic polymorphic ventricular tachycardia;Familial isolated arrhythmogenic ventricular dysplasia, biventricular form;Familial isolated arrhythmogenic ventricular dysplasia, left dominant form. The disease is caused by mutations affecting the gene represented in this entry.  The disease is caused by mutations affecting the gene represented in this entry.
== Function ==
[https://www.uniprot.org/uniprot/RYR2_HUMAN RYR2_HUMAN] Calcium channel that mediates the release of Ca(2+) from the sarcoplasmic reticulum into the cytoplasm and thereby plays a key role in triggering cardiac muscle contraction. Aberrant channel activation can lead to cardiac arrhythmia. In cardiac myocytes, calcium release is triggered by increased Ca(2+) levels due to activation of the L-type calcium channel CACNA1C. The calcium channel activity is modulated by formation of heterotetramers with RYR3. Required for cellular calcium ion homeostasis. Required for embryonic heart development.<ref>PMID:10830164</ref> <ref>PMID:20056922</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Heart failure, the leading cause of mortality and morbidity in the developed world, is characterized by cardiac ryanodine receptor 2 channels that are hyperphosphorylated, oxidized, and depleted of the stabilizing subunit calstabin-2. This results in a diastolic sarcoplasmic reticulum Ca(2+) leak that impairs cardiac contractility and triggers arrhythmias. Genetic mutations in ryanodine receptor 2 can also cause Ca(2+) leak, leading to arrhythmias and sudden cardiac death. Here, we solved the cryogenic electron microscopy structures of ryanodine receptor 2 variants linked either to heart failure or inherited sudden cardiac death. All are in the primed state, part way between closed and open. Binding of Rycal drugs to ryanodine receptor 2 channels reverts the primed state back towards the closed state, decreasing Ca(2+) leak, improving cardiac function, and preventing arrhythmias. We propose a structural-physiological mechanism whereby the ryanodine receptor 2 channel primed state underlies the arrhythmias in heart failure and arrhythmogenic disorders.

Structural basis for ryanodine receptor type 2 leak in heart failure and arrhythmogenic disorders.,Miotto MC, Reiken S, Wronska A, Yuan Q, Dridi H, Liu Y, Weninger G, Tchagou C, Marks AR Nat Commun. 2024 Sep 15;15(1):8080. doi: 10.1038/s41467-024-51791-y. PMID:39278969<ref>PMID:39278969</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 8uxh" style="background-color:#fffaf0;"></div>
== References ==
<references/>
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Marks AR]]
[[Category: Miotto MC]]