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TitleDantrolene inhibition of ryanodine receptor 1 carrying the severe malignant hyperthermia mutation Y522S visualized by cryo-EM.
Journal, issue, pagesStructure, Vol. 33, Issue 2, Page 338-348.e4, Year 2025
Publish dateFeb 6, 2025
AuthorsKavita A Iyer / Takuya Kobayashi / Takashi Murayama / Montserrat Samsó /
PubMed AbstractMutations 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 ...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.
External linksStructure / PubMed:39708816 / PubMed Central
MethodsEM (single particle)
Resolution3.23 - 3.34 Å
Structure data

EMDB-45493: Rabbit RyR1 disease mutant Y523S in complex with FKBP12.6, nanodisc and inhibitor dantrolene in the absence of calcium
Method: EM (single particle) / Resolution: 3.34 Å

EMDB-45497: Rabbit RyR1 disease mutant Y523S in complex with FKBP12.6, nanodisc and inhibitor dantrolene in the presence of activating calcium
Method: EM (single particle) / Resolution: 3.23 Å

45584

9cgp

EMDB-45584, PDB-9cgp:
RyR1 disease mutant Y523S with FKBP12.6, nanodisc and inhibitor dantrolene in the absence of calcium with refined P1 domain
Method: EM (single particle) / Resolution: 3.34 Å

Chemicals

ChemComp-ZN:
Unknown entry

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


ChemComp, No image

ChemComp-U1C:
Unknown entry

Source
  • oryctolagus cuniculus (rabbit)
  • homo sapiens (human)
KeywordsMEMBRANE PROTEIN / Ryanodine receptor / Calcium channel / Mutation / Y523S / RyR1 / dantrolene

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