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| Title | Symmetry-driven gating of TRPM8 by PIP and menthol. |
|---|---|
| Journal, issue, pages | Nat Commun, Vol. 17, Issue 1, Year 2026 |
| Publish date | Jul 21, 2026 |
Authors | Sun-Hong Kim / Chansik Hong / Hyunwoo Park / Youngchang Ju / Youngsoo Hwang / Jinhyeong Kim / Sangho Ji / Wookyung Yu / Insuk So / Hyung Ho Lee / ![]() |
| 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 ...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 links | Nat Commun / PubMed:42481499 / PubMed Central |
| Methods | EM (single particle) |
| Resolution | 2.81 - 4.09 Å |
| Structure data | EMDB-65116, PDB-9vjn: EMDB-65117, PDB-9vjo: EMDB-65118, PDB-9vjp: EMDB-65119, PDB-9vjq: EMDB-65120, PDB-9vjr: EMDB-65204, PDB-9vn9: EMDB-65205, PDB-9vna: EMDB-65206, PDB-9vnb: EMDB-65207, PDB-9vnc: ![]() EMDB-69908: Cryo-EM structure of TRP melastatin channel in the desensitized state, with icilin (10min) ![]() EMDB-69909: Cryo-EM structure of TRP melastatin channel with icilin (10min) ![]() EMDB-69929: Cryo-EM structure of TRP melastatin channel in the putative intermediate 3, without CHS ![]() EMDB-69930: Cryo-EM structure of TRP melastatin channel in the putative desensitized state, without CHS ![]() EMDB-69932: Cryo-EM structure of TRP melastatin channel in the putative intermediate 2 state, with EGTA ![]() EMDB-69933: Cryo-EM structure of TRP melastatin channel in the putative twofold intermediate 1 state, with EGTA ![]() EMDB-69934: Cryo-EM structure of TRP melastatin channel in the putative desensitized state, with EGTA |
| Chemicals | ![]() ChemComp-Y01: ![]() ChemComp-POV: ![]() ChemComp-PIO: ![]() ChemComp-CA: ![]()
ChemComp-XUQ: ![]() ChemComp-KX7: ![]() ChemComp-CLR: |
| Source |
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Keywords | MEMBRANE PROTEIN / TRP |
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