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Structure paper

TitleStructural basis for simvastatin-induced skeletal muscle weakness associated with type 1 ryanodine receptor T4709M mutation.
Journal, issue, pagesJ Clin Invest, Vol. 135, Issue 24, Year 2025
Publish dateDec 15, 2025
AuthorsGunnar Weninger / Haikel Dridi / Steven Reiken / Qi Yuan / Nan Zhao / Linda Groom / Jennifer Leigh / Yang Liu / Carl Tchagou / Jiayi Kang / Alexander Chang / Estefania Luna-Figueroa / Marco C Miotto / Anetta Wronska / Robert T Dirksen / Andrew R Marks /
PubMed AbstractStatins 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; ...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.
External linksJ Clin Invest / PubMed:41392983 / PubMed Central
MethodsEM (single particle)
Resolution2.2 - 3.5 Å
Structure data

49534

9nmn

EMDB-49534, PDB-9nmn:
Structure of mouse RyR1 (Ca2+/CFF/ATP dataset; open pore)
Method: EM (single particle) / Resolution: 3.09 Å

49535

9nmo

EMDB-49535, PDB-9nmo:
Structure of mouse RyR1 (Ca2+/CFF/ATP dataset; closed pore)
Method: EM (single particle) / Resolution: 2.4 Å

49536

9nmp

EMDB-49536, PDB-9nmp:
Structure of mouse RyR1 with simvastatin (Ca2+/CFF/ATP dataset; open pore)
Method: EM (single particle) / Resolution: 3.09 Å

49537

9nmq

EMDB-49537, PDB-9nmq:
Structure of mouse RyR1 with simvastatin (Ca2+/CFF/ATP dataset; closed pore)
Method: EM (single particle) / Resolution: 2.6 Å

49538

9nmr

EMDB-49538, PDB-9nmr:
Structure of mouse RyR1 (including auxiliary transmembrane helix TMx; EGTA-only dataset)
Method: EM (single particle) / Resolution: 2.91 Å

EMDB-73147: Constituent EM map: Focused refinement on NTD+SPRY+Calstabin-1 of mouse RyR1 (including auxiliary transmembrane helix TMx; EGTA-only dataset)
Method: EM (single particle) / Resolution: 2.6 Å

EMDB-73148: Constituent EM map: Focused refinement on JSol+CSol of mouse RyR1 (including auxiliary transmembrane helix TMx; EGTA-only dataset)
Method: EM (single particle) / Resolution: 2.6 Å

EMDB-73149: Constituent EM map: Focused refinement on BSol of mouse RyR1 (including auxiliary transmembrane helix TMx; EGTA-only dataset)
Method: EM (single particle) / Resolution: 2.9 Å

EMDB-73151: Constituent EM map: Focused refinement on Ry12 of mouse RyR1 (including auxiliary transmembrane helix TMx; EGTA-only dataset)
Method: EM (single particle) / Resolution: 2.9 Å

EMDB-73152: Constituent EM map: Focused refinement on Ry34 of mouse RyR1 (including auxiliary transmembrane helix TMx; EGTA-only dataset)
Method: EM (single particle) / Resolution: 2.9 Å

EMDB-73154: Constituent EM map: Focused refinement on NTD+SPRY+Calstabin-1 of mouse RyR1 (Ca2+/CFF/ATP dataset; closed pore)
Method: EM (single particle) / Resolution: 2.2 Å

EMDB-73155: Constituent EM map: Focused refinement on JSol+CSol of mouse RyR1 (Ca2+/CFF/ATP dataset; closed pore)
Method: EM (single particle) / Resolution: 2.2 Å

EMDB-73156: Constituent EM map: Focused refinement on BSol of mouse RyR1 (Ca2+/CFF/ATP dataset; closed pore)
Method: EM (single particle) / Resolution: 2.45 Å

EMDB-73157: Constituent EM map: Focused refinement on Ry12 of mouse RyR1 (Ca2+/CFF/ATP dataset; closed pore)
Method: EM (single particle) / Resolution: 2.45 Å

EMDB-73158: Constituent EM map: Focused refinement on Ry34 of mouse RyR1 (Ca2+/CFF/ATP dataset; closed pore)
Method: EM (single particle) / Resolution: 2.6 Å

EMDB-73159: Constituent EM map: Focused refinement on NTD+SPRY+Calstabin-1 of mouse RyR1 (Ca2+/CFF/ATP dataset; open pore)
Method: EM (single particle) / Resolution: 2.7 Å

EMDB-73160: Constituent EM map: Focused refinement on JSol+CSol of mouse RyR1 (Ca2+/CFF/ATP dataset; open pore)
Method: EM (single particle) / Resolution: 2.7 Å

EMDB-73161: Constituent EM map: Focused refinement on BSol of mouse RyR1 (Ca2+/CFF/ATP dataset; open pore)
Method: EM (single particle) / Resolution: 3.0 Å

EMDB-73162: Constituent EM map: Focused refinement on Ry12 of mouse RyR1 (Ca2+/CFF/ATP dataset; open pore)
Method: EM (single particle) / Resolution: 2.9 Å

EMDB-73163: Constituent EM map: Focused refinement on Ry34 of mouse RyR1 (Ca2+/CFF/ATP dataset; open pore)
Method: EM (single particle) / Resolution: 3.1 Å

EMDB-73164: Constituent EM map: Focused refinement on NTD+SPRY+Calstabin-1 of mouse RyR1 with simvastatin (Ca2+/CFF/ATP dataset; open pore)
Method: EM (single particle) / Resolution: 2.7 Å

EMDB-73165: Constituent EM map: Focused refinement on JSol+CSol of mouse RyR1 with simvastatin (Ca2+/CFF/ATP dataset; open pore)
Method: EM (single particle) / Resolution: 2.7 Å

EMDB-73166: Constituent EM map: Focused refinement on BSol of mouse RyR1 with simvastatin (Ca2+/CFF/ATP dataset; open pore)
Method: EM (single particle) / Resolution: 3.1 Å

EMDB-73167: Constituent EM map: Focused refinement on Ry12 of mouse RyR1 with simvastatin (Ca2+/CFF/ATP dataset; open pore)
Method: EM (single particle) / Resolution: 3.2 Å

EMDB-73169: Constituent EM map: Focused refinement on Ry34 of mouse RyR1 with simvastatin (Ca2+/CFF/ATP dataset; open pore)
Method: EM (single particle) / Resolution: 3.5 Å

EMDB-73170: Constituent EM map: Focused refinement on NTD+SPRY+Calstabin-1 of mouse RyR1 with simvastatin (Ca2+/CFF/ATP dataset; closed pore)
Method: EM (single particle) / Resolution: 2.3 Å

EMDB-73171: Constituent EM map: Focused refinement on JSol+CSol of mouse RyR1 with simvastatin (Ca2+/CFF/ATP dataset; closed pore)
Method: EM (single particle) / Resolution: 2.3 Å

EMDB-73172: Constituent EM map: Focused refinement on BSol of mouse RyR1 with simvastatin (Ca2+/CFF/ATP dataset; closed pore)
Method: EM (single particle) / Resolution: 2.7 Å

EMDB-73177: Constituent EM map: Focused refinement on Ry12 of mouse RyR1 with simvastatin (Ca2+/CFF/ATP dataset; closed pore)
Method: EM (single particle) / Resolution: 2.7 Å

EMDB-73180: Constituent EM map: Focused refinement on Ry34 of mouse RyR1 with simvastatin (Ca2+/CFF/ATP dataset; closed pore)
Method: EM (single particle) / Resolution: 2.95 Å

Chemicals

ChemComp-ZN:
Unknown entry

ChemComp-CFF:
CAFFEINE / medication*YM

ChemComp-ATP:
ADENOSINE-5'-TRIPHOSPHATE / ATP, energy-carrying molecule*YM

ChemComp-CA:
Unknown entry

ChemComp-PCW:
1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE / DOPC, phospholipid*YM

PDB-1byz:
DESIGNED PEPTIDE ALPHA-1, P1 FORM

Source
  • mus musculus (house mouse)
KeywordsTRANSPORT PROTEIN / Calcium / Ion Channel

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