6NR2

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

Summary for 6NR2

• Entry DOI: 10.2210/pdb6nr2/pdb
• EMDB information: 0487 0488 0489
• Descriptor: 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)
• Functional Keywords: 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
• Biological source: Ficedula albicollis (Collared flycatcher); More
• Total number of polymer chains: 4
• Total formula weight: 525659.81

Authors

Yin, Y.,Le, S.C.,Hsu, A.L.,Borgnia, M.J.,Yang, H.,Lee, S.-Y. (deposition date: 2019-01-22, release date: 2019-02-20, Last modification date: 2024-10-30)

Primary citation

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

Experimental method

ELECTRON MICROSCOPY (4 Å)