9VJP
Cryo-EM structure of TRP melastatin channel in the intermediate 2 state
Summary for 9VJP
| Entry DOI | 10.2210/pdb9vjp/pdb |
| EMDB information | 65118 |
| Descriptor | Transient receptor potential cation channel subfamily M member 8, [(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, CALCIUM ION (3 entities in total) |
| Functional Keywords | trp, membrane protein |
| Biological source | Mus musculus (house mouse) |
| Total number of polymer chains | 4 |
| Total formula weight | 520754.80 |
| 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 Cited by 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: 42481499DOI: 10.1038/s41467-026-75793-0 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (3.29 Å) |
Structure validation
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