National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)
R56HL144929
米国
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)
R01NS111031
米国
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)
R01HL153219
米国
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)
R01NS112363
米国
American Heart Association
20POST35120556
米国
引用
ジャーナル: Nat Struct Mol Biol / 年: 2021 タイトル: Structures of the TRPM5 channel elucidate mechanisms of activation and inhibition. 著者: Zheng Ruan / Emery Haley / Ian J Orozco / Mark Sabat / Richard Myers / Rebecca Roth / Juan Du / Wei Lü / 要旨: The Ca-activated TRPM5 channel plays essential roles in taste perception and insulin secretion. However, the mechanism by which Ca regulates TRPM5 activity remains elusive. We report cryo-EM ...The Ca-activated TRPM5 channel plays essential roles in taste perception and insulin secretion. However, the mechanism by which Ca regulates TRPM5 activity remains elusive. We report cryo-EM structures of the zebrafish TRPM5 in an apo closed state, a Ca-bound open state, and an antagonist-bound inhibited state. We define two novel ligand binding sites: a Ca site (Ca) in the intracellular domain and an antagonist site in the transmembrane domain (TMD). The Ca site is unique to TRPM5 and has two roles: modulating the voltage dependence and promoting Ca binding to the Ca site, which is conserved throughout TRPM channels. Conformational changes initialized from both Ca sites cooperatively open the ion-conducting pore. The antagonist NDNA wedges into the space between the S1-S4 domain and pore domain, stabilizing the transmembrane domain in an apo-like closed state. Our results lay the foundation for understanding the voltage-dependent TRPM channels and developing new therapeutic agents.