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
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)
R01NS111031
米国
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)
R01NS129804
米国
Other private
McKnight Scholar Award
Other private
Klingenstein-Simon Scholar
Other private
Sloan Research Fellowship
Other private
Pew Scholar
American Heart Association
24POST1196982
米国
引用
ジャーナル: Nature / 年: 2024 タイトル: Physiological temperature drives TRPM4 ligand recognition and gating. 著者: Jinhong Hu / Sung Jin Park / Tyler Walter / Ian J Orozco / Garrett O'Dea / Xinyu Ye / Juan Du / Wei Lü / 要旨: Temperature profoundly affects macromolecular function, particularly in proteins with temperature sensitivity. However, its impact is often overlooked in biophysical studies that are typically ...Temperature profoundly affects macromolecular function, particularly in proteins with temperature sensitivity. However, its impact is often overlooked in biophysical studies that are typically performed at non-physiological temperatures, potentially leading to inaccurate mechanistic and pharmacological insights. Here we demonstrate temperature-dependent changes in the structure and function of TRPM4, a temperature-sensitive Ca-activated ion channel. By studying TRPM4 prepared at physiological temperature using single-particle cryo-electron microscopy, we identified a 'warm' conformation that is distinct from those observed at lower temperatures. This conformation is driven by a temperature-dependent Ca-binding site in the intracellular domain, and is essential for TRPM4 function in physiological contexts. We demonstrated that ligands, exemplified by decavanadate (a positive modulator) and ATP (an inhibitor), bind to different locations of TRPM4 at physiological temperatures than at lower temperatures, and that these sites have bona fide functional relevance. We elucidated the TRPM4 gating mechanism by capturing structural snapshots of its different functional states at physiological temperatures, revealing the channel opening that is not observed at lower temperatures. Our study provides an example of temperature-dependent ligand recognition and modulation of an ion channel, underscoring the importance of studying macromolecules at physiological temperatures. It also provides a potential molecular framework for deciphering how thermosensitive TRPM channels perceive temperature changes.
全体 : Cryo-EM structure of the human TRPM4 channel in complex with calc...
全体
名称: Cryo-EM structure of the human TRPM4 channel in complex with calcium, decavanadate and ATP at 37 degrees Celsius
要素
複合体: Cryo-EM structure of the human TRPM4 channel in complex with calcium, decavanadate and ATP at 37 degrees Celsius
タンパク質・ペプチド: Transient receptor potential cation channel subfamily M
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超分子 #1: Cryo-EM structure of the human TRPM4 channel in complex with calc...
超分子
名称: Cryo-EM structure of the human TRPM4 channel in complex with calcium, decavanadate and ATP at 37 degrees Celsius タイプ: complex / ID: 1 / 親要素: 0 / 含まれる分子: all
由来(天然)
生物種: Homo sapiens (ヒト)
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分子 #1: Transient receptor potential cation channel subfamily M