8UXM
Structure of PKA phosphorylated human RyR2-R420W in the open state in the presence of calcium and calmodulin
This is a non-PDB format compatible entry.
Summary for 8UXM
| Entry DOI | 10.2210/pdb8uxm/pdb |
| EMDB information | 42769 |
| Descriptor | Calmodulin-1, Ryanodine receptor 2, Peptidyl-prolyl cis-trans isomerase FKBP1B, ... (6 entities in total) |
| Functional Keywords | calcium channel, membrane protein |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 12 |
| Total formula weight | 2380985.33 |
| Authors | Miotto, M.C.,Marks, A.R. (deposition date: 2023-11-09, release date: 2023-11-22, Last modification date: 2024-10-16) |
| Primary citation | Miotto, M.C.,Reiken, S.,Wronska, A.,Yuan, Q.,Dridi, H.,Liu, Y.,Weninger, G.,Tchagou, C.,Marks, A.R. Structural basis for ryanodine receptor type 2 leak in heart failure and arrhythmogenic disorders. Nat Commun, 15:8080-8080, 2024 Cited by PubMed Abstract: 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 leak that impairs cardiac contractility and triggers arrhythmias. Genetic mutations in ryanodine receptor 2 can also cause Ca 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 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. PubMed: 39278969DOI: 10.1038/s41467-024-51791-y PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (3.56 Å) |
Structure validation
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