8uq3

From Proteopedia

(Difference between revisions)

Current revision

Structure of human RyR2-S2808D in the closed state in the presence of ARM210

Structural highlights

8uq3 is a 8 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Electron Microscopy, Resolution 3.18Å
Ligands:	, ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

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

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.^[1] ^[2]

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^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Marx SO, Reiken S, Hisamatsu Y, Jayaraman T, Burkhoff D, Rosemblit N, Marks AR. PKA phosphorylation dissociates FKBP12.6 from the calcium release channel (ryanodine receptor): defective regulation in failing hearts. Cell. 2000 May 12;101(4):365-76. PMID:10830164
↑ Neef S, Dybkova N, Sossalla S, Ort KR, Fluschnik N, Neumann K, Seipelt R, Schondube FA, Hasenfuss G, Maier LS. CaMKII-dependent diastolic SR Ca2+ leak and elevated diastolic Ca2+ levels in right atrial myocardium of patients with atrial fibrillation. Circ Res. 2010 Apr 2;106(6):1134-44. doi: 10.1161/CIRCRESAHA.109.203836. Epub, 2010 Jan 7. PMID:20056922 doi:http://dx.doi.org/10.1161/CIRCRESAHA.109.203836
↑ Miotto MC, Reiken S, Wronska A, Yuan Q, Dridi H, Liu Y, Weninger G, Tchagou C, Marks AR. Structural basis for ryanodine receptor type 2 leak in heart failure and arrhythmogenic disorders. Nat Commun. 2024 Sep 15;15(1):8080. PMID:39278969 doi:10.1038/s41467-024-51791-y

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/8uq3"

Categories: Homo sapiens | Large Structures | Marks AR | Miotto MC

@@ Line 5: / Line 5: @@
 <table><tr><td colspan='2'>[[8uq3]] 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=8UQ3 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8UQ3 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]] 3.18&#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=KVR:4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methyl]benzoic+acid'>KVR</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></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=KVR:4-[(7-methoxy-3,5-dihydro-2~{H}-1,4-benzothiazepin-4-yl)methyl]benzoic+acid'>KVR</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=8uq3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8uq3 OCA], [https://pdbe.org/8uq3 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8uq3 RCSB], [https://www.ebi.ac.uk/pdbsum/8uq3 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8uq3 ProSAT]</span></td></tr>
 </table>

8uq3

From Proteopedia

Current revision

Structure of human RyR2-S2808D in the closed state in the presence of ARM210

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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