2025-11-26 カナダ・ブリティッシュコロンビア大学(UBC)
This illustration, based on what researchers were able to observe using high-resolution macromolecular cryo-electron microscopy, shows statin moelcules in black binding to the RyR1 protein. (Source: The Bioelectricity Lab, UBC Life Sciences Institute)
<関連情報>
- https://news.ubc.ca/2025/11/ubc-statins-muscles-research/
- https://www.nature.com/articles/s41467-025-66522-0
クライオ電子顕微鏡により、スタチントリプレットによるリアノジン受容体への連続的な結合と活性化が明らかになった Cryo-electron microscopy reveals sequential binding and activation of Ryanodine Receptors by statin triplets
Steven Molinarolo,Carmen R. Valdivia,Héctor H. Valdivia & Filip Van Petegem
Nature Communications Published:20 November 2025
DOI:https://doi.org/10.1038/s41467-025-66522-0
We are providing an unedited version of this manuscript to give early access to its findings. Before final publication, the manuscript will undergo further editing. Please note there may be errors present which affect the content, and all legal disclaimers apply.
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.
