9CGP

RyR1 disease mutant Y523S with FKBP12.6, nanodisc and inhibitor dantrolene in the absence of calcium with refined P1 domain

This is a non-PDB format compatible entry.

Summary for 9CGP

• Entry DOI: 10.2210/pdb9cgp/pdb
• Related: 7T64 7T65
• EMDB information: 45584 45585 45947
• Descriptor: Ryanodine receptor 1, Peptidyl-prolyl cis-trans isomerase FKBP1B, ZINC ION, ... (5 entities in total)
• Functional Keywords: ryanodine receptor, calcium channel, mutation, y523s, ryr1, dantrolene, membrane protein
• Biological source: Oryctolagus cuniculus (rabbit); More
• Total number of polymer chains: 8
• Total formula weight: 2313546.84

Authors

Iyer, K.A.,Samso, M. (deposition date: 2024-06-30, release date: 2024-12-11, Last modification date: 2025-02-19)

Primary citation

Iyer, K.A.,Kobayashi, T.,Murayama, T.,Samso, M.
Dantrolene inhibition of ryanodine receptor 1 carrying the severe malignant hyperthermia mutation Y522S visualized by cryo-EM.
Structure, 33:338-348.e4, 2025

PubMed Abstract: Mutations in the skeletal isoform of the ryanodine receptor 1 (RyR1) pose grave risks during anesthesia or treatment with succinylcholine muscle relaxants. These can trigger a potentially lethal malignant hyperthermia (MH) episode via intracellular calcium increase mainly from RyR1 channel leakage. Dantrolene is the only known treatment option to prevent death. The main target of dantrolene is RyR1; however, little is known about the mechanism of inhibition. Cryoelectron microscopy (cryo-EM) structures of dantrolene bound to the severe MH Y522S RyR1 mutant in the closed and open states at 2.5-3.3 Å resolution revealed that the drug binds to the channel's cytoplasmic assembly, far from the ion gate, interacting with residues W882, W996, and R1000 in the P1 domain. The finding was validated by Ca imaging and [H]ryanodine binding in wild-type (WT) and alanine mutants. Dantrolene reduced channel opening probability by restricting the central activation module, "cooling down" the primed conformation caused by the mutation.

PubMed: 39708816
DOI: 10.1016/j.str.2024.11.018

Experimental method

ELECTRON MICROSCOPY (3.34 Å)