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-Structure paper
Title | Structural insights into TRPM8 inhibition and desensitization. |
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Journal, issue, pages | Science, Vol. 365, Issue 6460, Page 1434-1440, Year 2019 |
Publish date | Sep 27, 2019 |
Authors | Melinda M Diver / Yifan Cheng / David Julius / |
PubMed Abstract | The transient receptor potential melastatin 8 (TRPM8) ion channel is the primary detector of environmental cold and an important target for treating pathological cold hypersensitivity. Here, we ...The transient receptor potential melastatin 8 (TRPM8) ion channel is the primary detector of environmental cold and an important target for treating pathological cold hypersensitivity. Here, we present cryo-electron microscopy structures of TRPM8 in ligand-free, antagonist-bound, or calcium-bound forms, revealing how robust conformational changes give rise to two nonconducting states, closed and desensitized. We describe a malleable ligand-binding pocket that accommodates drugs of diverse chemical structures, and we delineate the ion permeation pathway, including the contribution of lipids to pore architecture. Furthermore, we show that direct calcium binding mediates stimulus-evoked desensitization, clarifying this important mechanism of sensory adaptation. We observe large rearrangements within the S4-S5 linker that reposition the S1-S4 and pore domains relative to the TRP helix, leading us to propose a distinct model for modulation of TRPM8 and possibly other TRP channels. |
External links | Science / PubMed:31488702 / PubMed Central |
Methods | EM (single particle) |
Resolution | 3.0 - 3.6 Å |
Structure data | EMDB-0631, PDB-6o6a: EMDB-0636, PDB-6o6r: |
Chemicals | ChemComp-Y01: ChemComp-NA: ChemComp-UND: ChemComp-9PE: ChemComp-LQ7: ChemComp-T14: ChemComp-CA: |
Source |
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Keywords | TRANSPORT PROTEIN / Ion Channel / TRPM8 |