8UQ4

Structure of human RyR2-S2808D in the subprimed state in the presence of H2O2/NOC-12/GSH

これはPDB形式変換不可エントリーです。

8UQ4 の概要

• エントリーDOI: 10.2210/pdb8uq4/pdb
• EMDBエントリー: 42460
• 分子名称: Ryanodine receptor 2, Peptidyl-prolyl cis-trans isomerase FKBP1B, ZINC ION, ... (4 entities in total)
• 機能のキーワード: calcium channel, membrane protein
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 8
• 化学式量合計: 2312769.59

構造登録者

Miotto, M.C.,Marks, A.R. (登録日: 2023-10-23, 公開日: 2023-11-15, 最終更新日: 2024-10-23)

主引用文献

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

実験手法

ELECTRON MICROSCOPY (3.64 Å)