9B6E
Cryo-EM structure of the mouse TRPM8 channel in complex with the antagonist TC-I 2014
Summary for 9B6E
| Entry DOI | 10.2210/pdb9b6e/pdb |
| EMDB information | 44256 |
| Descriptor | Transient receptor potential cation channel subfamily M member 8, 3-{7-(trifluoromethyl)-5-[2-(trifluoromethyl)phenyl]-1H-benzimidazol-2-yl}-1-oxa-2-azaspiro[4.5]dec-2-ene, CHOLESTEROL HEMISUCCINATE (3 entities in total) |
| Functional Keywords | trpm8, menthol receptor, cold receptor, pi(4, 5)p2, cooling agonists, temperature sensing, ion channel, sensory transduction, transient receptor potential ion channel, trpm8 activation, trpm8 inhibition, trpm8 desensitization, trpm8 antagonists, membrane protein |
| Biological source | Mus musculus (house mouse) |
| Total number of polymer chains | 4 |
| Total formula weight | 535850.49 |
| Authors | Yin, Y.,Park, C.-G.,Zhang, F.,Fedor, J.,Feng, S.,Suo, Y.,Im, W.,Lee, S.-Y. (deposition date: 2024-03-25, release date: 2024-08-21, Last modification date: 2024-11-13) |
| Primary citation | Yin, Y.,Park, C.G.,Zhang, F.,G Fedor, J.,Feng, S.,Suo, Y.,Im, W.,Lee, S.Y. Mechanisms of sensory adaptation and inhibition of the cold and menthol receptor TRPM8. Sci Adv, 10:eadp2211-eadp2211, 2024 Cited by PubMed Abstract: Our sensory adaptation to cold and chemically induced coolness is mediated by the intrinsic property of TRPM8 channels to desensitize. TRPM8 is also implicated in cold-evoked pain disorders and migraine, highlighting its inhibitors as an avenue for pain relief. Despite the importance, the mechanisms of TRPM8 desensitization and inhibition remained unclear. We found, using cryo-electron microscopy, electrophysiology, and molecular dynamics simulations, that TRPM8 inhibitors bind selectively to the desensitized state of the channel. These inhibitors were used to reveal the overlapping mechanisms of desensitization and inhibition and that cold and cooling agonists share a common desensitization pathway. Furthermore, we identified the structural determinants crucial for the conformational change in TRPM8 desensitization. Our study illustrates how receptor-level conformational changes alter cold sensation, providing insights into therapeutic development. PubMed: 39093967DOI: 10.1126/sciadv.adp2211 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (2.91 Å) |
Structure validation
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