9OL4

Cryo-EM Structure of Ryanodine Receptor 1: Drug Bound Open Conformation

これはPDB形式変換不可エントリーです。

9OL4 の概要

• エントリーDOI: 10.2210/pdb9ol4/pdb
• EMDBエントリー: 70589
• 分子名称: Ryanodine receptor 1, Peptidyl-prolyl cis-trans isomerase FKBP1B, CAFFEINE, ... (6 entities in total)
• 機能のキーワード: ion channel, calcium channel, transport protein, transport protein-isomerase complex, transport protein/isomerase
• 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: 2319819.93

構造登録者

Molinarolo, S.M.,Van Petegem, F. (登録日: 2025-05-12, 公開日: 2026-01-28)

主引用文献

Molinarolo, S.,Valdivia, C.R.,Valdivia, H.H.,Van Petegem, F.
Cryo-electron microscopy reveals sequential binding and activation of Ryanodine Receptors by statin triplets.
Nat Commun, 16:11508-11508, 2025

PubMed Abstract: Statins are the most prescribed class of drugs and inhibit a key enzyme in the cholesterol biosynthesis pathway. Many patients have reported mild to severe muscle related symptoms and a subset are at risk for rhabdomyolysis. Sequence variants in RyR1, the skeletal muscle Ryanodine Receptor, correlate with intolerance to statins, but whether RyR1 can bind statins directly has remained unclear. Here we report cryo-EM structures of RyR1 in the absence and presence of atorvastatin, firmly establishing RyR1 as an unintended off-target. Our results show an unusual binding mode whereby three atorvastatin molecules bind together in a cleft formed by the pseudo-voltage sensing domain, making extensive interactions with each other and with RyR1. Atorvastatin activates RyR1 in a sequential way, whereby one statin per subunit can bind to the transmembrane region of a closed RyR1, with small structural perturbations that prime the channel for opening. Binding of two additional statins per subunit is associated with a widening of the pseudo-voltage sensing domain that triggers opening of the pore. Comparison with atorvastatin binding to HMG-CoA reductase, its intended target, offers clues on how to modify the statin to reduce RyR1 binding, while leaving binding to HMG-CoA reductase unperturbed.

PubMed: 41266329
DOI: 10.1038/s41467-025-66522-0

実験手法

ELECTRON MICROSCOPY (3.37 Å)