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TitleA drug and ATP binding site in type 1 ryanodine receptor.
Journal, issue, pagesStructure, Vol. 30, Issue 7, Page 1025-11034.e4, Year 2022
Publish dateJul 7, 2022
AuthorsZephan Melville / Haikel Dridi / Qi Yuan / Steven Reiken / Anetta Wronska / Yang Liu / Oliver B Clarke / Andrew R Marks /
PubMed AbstractThe ryanodine receptor (RyR)/calcium release channel on the sarcoplasmic reticulum (SR) is required for excitation-contraction coupling in skeletal and cardiac muscle. Inherited mutations and stress- ...The ryanodine receptor (RyR)/calcium release channel on the sarcoplasmic reticulum (SR) is required for excitation-contraction coupling in skeletal and cardiac muscle. Inherited mutations and stress-induced post-translational modifications result in an SR Ca leak that causes skeletal myopathies, heart failure, and exercise-induced sudden death. A class of therapeutics known as Rycals prevent the RyR-mediated leak, are effective in preventing disease progression and restoring function in animal models, and are in clinical trials for patients with muscle and heart disorders. Using cryogenic-electron microscopy, we present a model of RyR1 with a 2.45-Å resolution before local refinement, revealing a binding site in the RY1&2 domain (3.10 Å local resolution), where the Rycal ARM210 binds cooperatively with ATP and stabilizes the closed state of RyR1.
External linksStructure / PubMed:35580609
MethodsEM (single particle)
Resolution2.45 Å
Structure data

26205

7tzc

EMDB-26205, PDB-7tzc:
A drug and ATP binding site in type 1 ryanodine receptor
Method: EM (single particle) / Resolution: 2.45 Å

Chemicals

ChemComp-CA:
Unknown entry

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

ChemComp-ZN:
Unknown entry

ChemComp-CFF:
CAFFEINE / medication*YM

ChemComp-KVR:
4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methyl]benzoic acid

ChemComp-L9R:
(2S)-3-(octadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate / SOPC, phospholipid*YM

Source
  • oryctolagus cuniculus (rabbit)
  • homo sapiens (human)
KeywordsMEMBRANE PROTEIN / ryanodine receptor / calcium / ion channel / MEMBRANE PROTEIN-ISOMERASE complex

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