6NR2

Cryo-EM structure of the TRPM8 ion channel in complex with the menthol analog WS-12 and PI(4,5)P2

6NR2 の概要

• エントリーDOI: 10.2210/pdb6nr2/pdb
• EMDBエントリー: 0487 0488 0489
• 分子名称: Transient receptor potential cation channel subfamily M member 8, (2S)-1-{[(R)-hydroxy{[(1R,2R,3S,4R,5R,6S)-2,3,6-trihydroxy-4,5-bis(phosphonooxy)cyclohexyl]oxy}phosphoryl]oxy}-3-(octadecanoyloxy)propan-2-yl icosa-5,8,11,14-tetraenoate, (1R,2S,5R)-N-(4-methoxyphenyl)-5-methyl-2-(propan-2-yl)cyclohexane-1-carboxamide (3 entities in total)
• 機能のキーワード: ion channel, trp channel, trpm channel, trpm8 channel, cold sensing, lipid sensing, menthol, icilin, ws-12, pi(4, 5)p2, cooling agent, membrane protein, calcium-permeable ion channel, transport protein
• 由来する生物種: Ficedula albicollis (Collared flycatcher); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 525659.81

構造登録者

Yin, Y.,Le, S.C.,Hsu, A.L.,Borgnia, M.J.,Yang, H.,Lee, S.-Y. (登録日: 2019-01-22, 公開日: 2019-02-20, 最終更新日: 2024-10-30)

主引用文献

Yin, Y.,Le, S.C.,Hsu, A.L.,Borgnia, M.J.,Yang, H.,Lee, S.Y.
Structural basis of cooling agent and lipid sensing by the cold-activated TRPM8 channel.
Science, 363:-, 2019

PubMed Abstract: Transient receptor potential melastatin member 8 (TRPM8) is a calcium ion (Ca)-permeable cation channel that serves as the primary cold and menthol sensor in humans. Activation of TRPM8 by cooling compounds relies on allosteric actions of agonist and membrane lipid phosphatidylinositol 4,5-bisphosphate (PIP), but lack of structural information has thus far precluded a mechanistic understanding of ligand and lipid sensing by TRPM8. Using cryo-electron microscopy, we determined the structures of TRPM8 in complex with the synthetic cooling compound icilin, PIP, and Ca, as well as in complex with the menthol analog WS-12 and PIP Our structures reveal the binding sites for cooling agonists and PIP in TRPM8. Notably, PIP binds to TRPM8 in two different modes, which illustrate the mechanism of allosteric coupling between PIP and agonists. This study provides a platform for understanding the molecular mechanism of TRPM8 activation by cooling agents.

PubMed: 30733385
DOI: 10.1126/science.aav9334

実験手法

ELECTRON MICROSCOPY (4 Å)