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TitleSymmetry-driven gating of TRPM8 by PIP and menthol.
Journal, issue, pagesNat Commun, Vol. 17, Issue 1, Year 2026
Publish dateJul 21, 2026
AuthorsSun-Hong Kim / Chansik Hong / Hyunwoo Park / Youngchang Ju / Youngsoo Hwang / Jinhyeong Kim / Sangho Ji / Wookyung Yu / Insuk So / Hyung Ho Lee /
PubMed AbstractTRPM8, 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 ...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.
External linksNat Commun / PubMed:42481499 / PubMed Central
MethodsEM (single particle)
Resolution2.81 - 4.09 Å
Structure data

EMDB-65116, PDB-9vjn:
Cryo-EM structure of TRP melastatin channel in the closed state
Method: EM (single particle) / Resolution: 3.43 Å

EMDB-65117, PDB-9vjo:
Cryo-EM structure of TRP melastatin channel in the intermediate 1 state
Method: EM (single particle) / Resolution: 2.82 Å

EMDB-65118, PDB-9vjp:
Cryo-EM structure of TRP melastatin channel in the intermediate 2 state
Method: EM (single particle) / Resolution: 3.29 Å

EMDB-65119, PDB-9vjq:
Cryo-EM structure of TRP melastatin channel with menthol
Method: EM (single particle) / Resolution: 2.9 Å

EMDB-65120, PDB-9vjr:
Cryo-EM structure of TRP melastatin channel with icilin
Method: EM (single particle) / Resolution: 3.1 Å

EMDB-65204, PDB-9vn9:
Cryo-EM structure of TRP melastatin channel in the intermediate 3 state
Method: EM (single particle) / Resolution: 3.48 Å

EMDB-65205, PDB-9vna:
Cryo-EM structure of TRP melastatin channel in the desensitized state, with CHS
Method: EM (single particle) / Resolution: 3.25 Å

EMDB-65206, PDB-9vnb:
Cryo-EM structure of TRP melastatin channel in the desensitized state, without CHS
Method: EM (single particle) / Resolution: 2.81 Å

EMDB-65207, PDB-9vnc:
Cryo-EM structure of TRP melastatin channel in the desensitized state, with icilin
Method: EM (single particle) / Resolution: 3.45 Å

EMDB-69908: Cryo-EM structure of TRP melastatin channel in the desensitized state, with icilin (10min)
Method: EM (single particle) / Resolution: 3.46 Å

EMDB-69909: Cryo-EM structure of TRP melastatin channel with icilin (10min)
Method: EM (single particle) / Resolution: 3.08 Å

EMDB-69929: Cryo-EM structure of TRP melastatin channel in the putative intermediate 3, without CHS
Method: EM (single particle) / Resolution: 3.71 Å

EMDB-69930: Cryo-EM structure of TRP melastatin channel in the putative desensitized state, without CHS
Method: EM (single particle) / Resolution: 3.1 Å

EMDB-69932: Cryo-EM structure of TRP melastatin channel in the putative intermediate 2 state, with EGTA
Method: EM (single particle) / Resolution: 3.58 Å

EMDB-69933: Cryo-EM structure of TRP melastatin channel in the putative twofold intermediate 1 state, with EGTA
Method: EM (single particle) / Resolution: 4.09 Å

EMDB-69934: Cryo-EM structure of TRP melastatin channel in the putative desensitized state, with EGTA
Method: EM (single particle) / Resolution: 3.95 Å

Chemicals

ChemComp-Y01:
CHOLESTEROL HEMISUCCINATE

ChemComp-POV:
(2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate / phospholipid*YM

ChemComp-PIO:
[(2R)-2-octanoyloxy-3-[oxidanyl-[(1R,2R,3S,4R,5R,6S)-2,3,6-tris(oxidanyl)-4,5-diphosphonooxy-cyclohexyl]oxy-phosphoryl]oxy-propyl] octanoate

ChemComp-CA:
Unknown entry


ChemComp, No image

ChemComp-XUQ:
Unknown entry

ChemComp-KX7:
Icilin

ChemComp-CLR:
CHOLESTEROL

Source
  • mus musculus (house mouse)
KeywordsMEMBRANE PROTEIN / TRP

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