9NMQ

Structure of mouse RyR1 with simvastatin (Ca2+/CFF/ATP dataset; closed pore)

これはPDB形式変換不可エントリーです。

9NMQ の概要

• エントリーDOI: 10.2210/pdb9nmq/pdb
• EMDBエントリー: 49537
• 分子名称: Ryanodine receptor 1, Peptidyl-prolyl cis-trans isomerase FKBP1A, ZINC ION, ... (8 entities in total)
• 機能のキーワード: calcium, ion channel, transport protein
• 由来する生物種: Mus musculus (house mouse); 詳細
• タンパク質・核酸の鎖数: 8
• 化学式量合計: 2325430.42

構造登録者

Weninger, G.,Marks, A.R. (登録日: 2025-03-04, 公開日: 2025-10-08, 最終更新日: 2025-12-24)

主引用文献

Weninger, G.,Dridi, H.,Reiken, S.,Yuan, Q.,Zhao, N.,Groom, L.,Leigh, J.,Liu, Y.,Tchagou, C.,Kang, J.,Chang, A.,Luna-Figueroa, E.,Miotto, M.C.,Wronska, A.,Dirksen, R.T.,Marks, A.R.
Structural basis for simvastatin-induced skeletal muscle weakness associated with type 1 ryanodine receptor T4709M mutation.
J.Clin.Invest., 135:-, 2025

PubMed Abstract: Statins lower cholesterol, reducing the risk of heart disease, and are among the most frequently prescribed drugs. Approximately 10% of individuals develop statin-associated muscle symptoms (SAMS; myalgias, rhabdomyolysis, and muscle weakness), often rendering them statin intolerant. The mechanism underlying SAMS remains poorly understood. Patients with mutations in the skeletal muscle ryanodine receptor 1 (RyR1)/calcium release channel can be particularly intolerant of statins. High-resolution structures revealed simvastatin binding sites in the pore region of RyR1. Simvastatin stabilized the open conformation of the pore and activated the RyR1 channel. In a mouse expressing a mutant RyR1-T4709M found in a patient with profound statin intolerance, simvastatin caused muscle weakness associated with leaky RyR1 channels. Cotreatment with a Rycal drug that stabilizes the channel closed state prevented simvastatin-induced muscle weakness. Thus, statin binding to RyR1 can cause SAMS, and patients with RyR1 mutations may represent a high-risk group for statin intolerance.

PubMed: 41392983
DOI: 10.1172/JCI194490

実験手法

ELECTRON MICROSCOPY (2.6 Å)