9B6D

Cryo-EM structure of the mouse TRPM8 channel in the ligand-free desensitized state

9B6D の概要

• エントリーDOI: 10.2210/pdb9b6d/pdb
• EMDBエントリー: 44255
• 分子名称: Transient receptor potential cation channel subfamily M member 8, CHOLESTEROL HEMISUCCINATE (2 entities in total)
• 機能のキーワード: trpm8, menthol receptor, cold receptor, pi(4, 5)p2, cooling agonists, temperature sensing, ion channel, sensory transduction, transient receptor potential ion channel, trpm8 activation, trpm8 inhibition, trpm8 desensitization, trpm8 antagonists, membrane protein
• 由来する生物種: Mus musculus (house mouse)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 535927.77

構造登録者

Yin, Y.,Park, C.-G.,Zhang, F.,Fedor, J.,Feng, S.,Suo, Y.,Im, W.,Lee, S.-Y. (登録日: 2024-03-25, 公開日: 2024-08-21, 最終更新日: 2024-11-20)

主引用文献

Yin, Y.,Park, C.G.,Zhang, F.,G Fedor, J.,Feng, S.,Suo, Y.,Im, W.,Lee, S.Y.
Mechanisms of sensory adaptation and inhibition of the cold and menthol receptor TRPM8.
Sci Adv, 10:eadp2211-eadp2211, 2024

PubMed Abstract: Our sensory adaptation to cold and chemically induced coolness is mediated by the intrinsic property of TRPM8 channels to desensitize. TRPM8 is also implicated in cold-evoked pain disorders and migraine, highlighting its inhibitors as an avenue for pain relief. Despite the importance, the mechanisms of TRPM8 desensitization and inhibition remained unclear. We found, using cryo-electron microscopy, electrophysiology, and molecular dynamics simulations, that TRPM8 inhibitors bind selectively to the desensitized state of the channel. These inhibitors were used to reveal the overlapping mechanisms of desensitization and inhibition and that cold and cooling agonists share a common desensitization pathway. Furthermore, we identified the structural determinants crucial for the conformational change in TRPM8 desensitization. Our study illustrates how receptor-level conformational changes alter cold sensation, providing insights into therapeutic development.

PubMed: 39093967
DOI: 10.1126/sciadv.adp2211

実験手法

ELECTRON MICROSCOPY (3.3 Å)