Database of articles cited by EMDB/PDB/SASBDB data

Keywords
Structure methods	All X-ray diffraction NMR electron microscopy small angle scattering neutron diffraction fiber diffraction powder diffraction infrared spectroscopy EPR fluorescence transfer theoretical model Hybrid
Author
Journal
IF	>30 >20 >10 >5 all

Title	Cryo-electron microscopy reveals sequential binding and activation of Ryanodine Receptors by statin triplets.
Journal, issue, pages	Nat Commun, Vol. 16, Issue 1, Page 11508, Year 2025
Publish date	Nov 20, 2025
Authors	Steven Molinarolo / Carmen R Valdivia / Héctor H Valdivia / Filip Van Petegem /
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 ...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.
External links	Nat Commun / PubMed:41266329 / PubMed Central
Methods	EM (single particle)
Resolution	2.85 - 4.08 Å
Structure data	EMDB-70574: Cryo-EM Structure of Ryanodine Receptor 1: DMSO Control Consensus Map Method: EM (single particle) / Resolution: 3.11 Å EMDB-70575: Cryo-EM Structure of Ryanodine Receptor 1: DMSO Control N-terminal Domain Locally Refined Map Method: EM (single particle) / Resolution: 2.86 Å EMDB-70576: Cryo-EM Structure of Ryanodine Receptor 1: DMSO Control BSol Locally Refined Map Method: EM (single particle) / Resolution: 3.29 Å EMDB-70577: Cryo-EM Structure of Ryanodine Receptor 1: DMSO Control C-terminal Domain Locally Refined Map Method: EM (single particle) / Resolution: 3.09 Å EMDB-70578: Cryo-EM Structure of Ryanodine Receptor 1: DMSO Control Transmembrane Domain (C4) Locally Refined Map Method: EM (single particle) / Resolution: 2.85 Å EMDB-70579: Cryo-EM Structure of Ryanodine Receptor 1: Drug Bound Closed Conformation Consensus Map Method: EM (single particle) / Resolution: 3.56 Å EMDB-70580: Cryo-EM Structure of Ryanodine Receptor 1: Drug Bound Closed Conformation N-terminal Domain Locally Refined Map Method: EM (single particle) / Resolution: 3.13 Å EMDB-70581: Cryo-EM Structure of Ryanodine Receptor 1: Drug Bound Closed Conformation BSol Locally Refined Map Method: EM (single particle) / Resolution: 3.44 Å EMDB-70582: Cryo-EM Structure of Ryanodine Receptor 1: Drug Bound Closed Conformation C-terminal Domain Locally Refined Map Method: EM (single particle) / Resolution: 3.14 Å EMDB-70583: Cryo-EM Structure of Ryanodine Receptor 1: Drug Bound Closed Conformation Transmembrane Domain (C4) Locally Refined Map Method: EM (single particle) / Resolution: 3.19 Å 70591 9ol6 EMDB-70591: Cryo-EM Structure of Rabbit Ryanodine Receptor 1: DMSO Control Composite Map PDB-9ol6: Rabbit Ryanodine Receptor 1: DMSO Control Closed Conformation Method: EM (single particle) / Resolution: 3.11 Å EMDB-70599: Cryo-EM Structure of Pig Ryanodine Receptor 1 R615C Mutant: Drug Bound Open Conformation Consensus Map Method: EM (single particle) / Resolution: 3.36 Å EMDB-70600: Cryo-EM Structure of Pig Ryanodine Receptor 1 R615C Mutant: Drug Bound Closed Conformation Consensus Map Method: EM (single particle) / Resolution: 4.08 Å EMDB-71920: Cryo-EM Structure of Pig Ryanodine Receptor 1 R615C Mutant: Drug Bound Open Conformation Transmembrane Domain (C4) Locally Refined Map Method: EM (single particle) / Resolution: 3.16 Å EMDB-71921: Cryo-EM Structure of Pig Ryanodine Receptor 1 R615C Mutant: Drug Bound Open Conformation BSol Domain Locally Refined Map Method: EM (single particle) / Resolution: 3.26 Å EMDB-71922: Cryo-EM Structure of Pig Ryanodine Receptor 1 R615C Mutant: Drug Bound Open Conformation N-terminal Domain Locally Refined Map Method: EM (single particle) / Resolution: 2.94 Å EMDB-71923: Cryo-EM Structure of Pig Ryanodine Receptor 1 R615C Mutant: Drug Bound Open Conformation C-terminal Domain Locally Refined Map Method: EM (single particle) / Resolution: 3.0 Å 71924 9pwo EMDB-71924: Cryo-EM Structure of Pig Ryanodine Receptor 1 R615C Mutant: Atorvastatin Bound Open Conformation Composite Map PDB-9pwo: Pig Ryanodine Receptor 1 R615C Mutant: Atorvastatin Bound Open Conformation Method: EM (single particle) / Resolution: 3.36 Å
Chemicals	ChemComp-CA: Unknown entry ChemComp-ZN: Unknown entry ChemComp-CFF: CAFFEINE / medicationYM ChemComp-117*: 7-[2-(4-FLUORO-PHENYL)-5-ISOPROPYL-3-PHENYL-4-PHENYLCARBAMOYL-PYRROL-1-YL]- 3,5-DIHYDROXY-HEPTANOIC ACID
Source	oryctolagus cuniculus (rabbit) homo sapiens (human) sus scrofa (pig)
Keywords	TRANSPORT PROTEIN / Ion channel / Calcium Channel