National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)
R01HL145473
United States
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)
R01DK118240
United States
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)
R01HL142903
United States
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)
R01HL140934
United States
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)
R01AR070194
United States
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)
T32 HL120826
United States
Citation
Journal: Structure / Year: 2022 Title: A drug and ATP binding site in type 1 ryanodine receptor. Authors: Zephan Melville / Haikel Dridi / Qi Yuan / Steven Reiken / Anetta Wronska / Yang Liu / Oliver B Clarke / Andrew R Marks / Abstract: 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- ...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.
EMPIAR-10997 (Title: A drug and ATP binding site in type 1 ryanodine receptor Data size: 1.5 TB Data #1: Type-1 ryanodine receptor [micrographs - multiframe])
Model: Quantifoil R0.6/1 / Material: GOLD / Mesh: 300 / Support film - Material: GOLD / Support film - topology: HOLEY / Support film - Film thickness: 50.0 nm
Vitrification
Cryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 4 K / Instrument: FEI VITROBOT MARK IV
-
Electron microscopy
Microscope
FEI TITAN KRIOS
Image recording
Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Number grids imaged: 1 / Number real images: 6862 / Average exposure time: 2.5 sec. / Average electron dose: 57.65 e/Å2
Electron beam
Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
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