8UQ5

Structure of human RyR2-S2808D in the primed state in the presence of Rapamycin

This is a non-PDB format compatible entry.

Summary for 8UQ5

• Entry DOI: 10.2210/pdb8uq5/pdb
• EMDB information: 42461
• Descriptor: Ryanodine receptor 2, ZINC ION, ADENOSINE-5'-TRIPHOSPHATE (3 entities in total)
• Functional Keywords: calcium channel, membrane protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 4
• Total formula weight: 2265575.58

Authors

Miotto, M.C.,Marks, A.R. (deposition date: 2023-10-23, release date: 2023-11-15, Last modification date: 2024-10-30)

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

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: 39278969
DOI: 10.1038/s41467-024-51791-y

Experimental method

ELECTRON MICROSCOPY (3.96 Å)