Zephan Melville

Abstract Malignant hyperthermia (MH) is a life-threatening pharmacogenetic condition triggered by volatile anesthetics, which activate pathogenic RyR1 mutants. The small molecule therapeutic dantrolene has long been used to treat MH. However, the binding site and mechanism of dantrolene remain unclear. Here, we present cryo-EM structures of RyR1 bound to dantrolene and the MH trigger agent 4-chloro-m-cresol (4CmC), revealing the dantrolene and 4CmC binding sites in atomic detail.

Acimovic I. Refaat M.M. Moreau A. Salykin A. Reiken S. Sleiman Y. Souidi M. Přibyl J. Kajava A.V. Richard S. et al. Post-translational modifications and diastolic calcium leak associated to the novel RyR2-D3638A mutation lead to CPVT in patient-specific hiPSC-derived cardiomyocytes. J. Clin. Med. 2018; 7: 423https://doi.org/10.3390/jcm7110423 Adams P.D. Afonine P.V. Bunkóczi G. Chen V.B. Davis I.W. Echols N. Headd J.J. Hung L.-W. Kapral G.J. Grosse-Kunstleve R.W. et al.

Highlights • High-resolution structures of RyR1 resolved in liposomes • The cryo-EM structure of RyR1 in liposomes closely matches detergent structures • The channel remains dynamic in liposomes Summary The type 1 ryanodine receptor (RyR)/calcium release channel on the sarcoplasmic reticulum (SR) is required for skeletal muscle excitation-contraction coupling and is the largest known ion channel, composed of four 565-kDa protomers.