National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIH/NIAMS)
R01 AR068431
米国
American Heart Association
19POST34430178
米国
Other private
MDA 352845
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)
U24 GM116789
米国
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)
U24 GM116790
米国
引用
ジャーナル: Structure / 年: 2025 タイトル: Dantrolene inhibition of ryanodine receptor 1 carrying the severe malignant hyperthermia mutation Y522S visualized by cryo-EM. 著者: Kavita A Iyer / Takuya Kobayashi / Takashi Murayama / Montserrat Samsó / 要旨: 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 ...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.
使用したクラス数: 3 / 解像度のタイプ: BY AUTHOR / 解像度: 3.34 Å / 解像度の算出法: OTHER / ソフトウェア - 名称: cryoSPARC (ver. 3.3.1) 詳細: The P1 domain (at the corners) was refined using focused alignment and combined with the original 3.34 A-resolution map 使用した粒子像数: 249034
初期 角度割当
タイプ: MAXIMUM LIKELIHOOD / ソフトウェア - 名称: cryoSPARC (ver. 3.3.1)