9VJN

Cryo-EM structure of TRP melastatin channel in the closed state

Summary for 9VJN

• Entry DOI: 10.2210/pdb9vjn/pdb
• EMDB information: 65116
• Descriptor: Transient receptor potential cation channel subfamily M member 8, CHOLESTEROL HEMISUCCINATE, (2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate (3 entities in total)
• Functional Keywords: trp, membrane protein
• Biological source: Mus musculus (house mouse)
• Total number of polymer chains: 4
• Total formula weight: 526489.24

Authors

Kim, S.-H.,Park, H.,Lee, H.H. (deposition date: 2025-06-21, release date: 2026-06-24, Last modification date: 2026-08-12)

Primary citation

Kim, S.H.,Hong, C.,Park, H.,Ju, Y.,Hwang, Y.,Kim, J.,Ji, S.,Yu, W.,So, I.,Lee, H.H.
Symmetry-driven gating of TRPM8 by PIP 2 and menthol.
Nat Commun, 17:-, 2026

PubMed Abstract: TRPM8, a cold-activated ion channel, enables mammals to sense cooling agents such as menthol. While PIP is essential for menthol-induced activation of TRPM8, the precise cooperative mechanism and the specific binding mode of menthol have remained elusive. Here, we present cryo-EM structures of mouse TRPM8 in diverse conformations, including a PIP-induced two-fold symmetric intermediate and an icilin-bound open state. Our results reveal that PIP binding initiates a symmetry-breaking event, priming the channel for activation through a noncanonical intermediate states. The subsequent binding of cooling agonists promotes a transition back to four-fold symmetry. Notably, we find that menthol stabilizes the PIP-bound state, thereby overcoming channel desensitization, while icilin, in concert with calcium, stabilizes a fully open conformation. Together, these structures illuminate a stepwise activation pathway involving distinct symmetry transitions and define the cooperative allosteric mechanism by which PIP and cooling agonists gate the channel.

PubMed: 42481499
DOI: 10.1038/s41467-026-75793-0

Experimental method

ELECTRON MICROSCOPY (3.43 Å)