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Structure paper

TitleStructural insights into TRPM8 inhibition and desensitization.
Journal, issue, pagesScience, Vol. 365, Issue 6460, Page 1434-1440, Year 2019
Publish dateSep 27, 2019
AuthorsMelinda M Diver / Yifan Cheng / David Julius /
PubMed AbstractThe 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 linksScience / PubMed:31488702 / PubMed Central
MethodsEM (single particle)
Resolution3 - 3.6 Å
Structure data

EMDB-0631, PDB-6o6a:
Structure of the TRPM8 cold receptor by single particle electron cryo-microscopy, ligand-free state
Method: EM (single particle) / Resolution: 3.6 Å

EMDB-0636, PDB-6o6r:
Structure of the TRPM8 cold receptor by single particle electron cryo-microscopy, AMTB-bound state
Method: EM (single particle) / Resolution: 3.2 Å

EMDB-0638, PDB-6o72:
Structure of the TRPM8 cold receptor by single particle electron cryo-microscopy, TC-I 2014-bound state
Method: EM (single particle) / Resolution: 3 Å

EMDB-0639, PDB-6o77:
Structure of the TRPM8 cold receptor by single particle electron cryo-microscopy, calcium-bound state
Method: EM (single particle) / Resolution: 3.2 Å

Chemicals

ChemComp-Y01:
CHOLESTEROL HEMISUCCINATE

ChemComp-NA:
SODIUM ION / Sodium

ChemComp-UND:
UNDECANE / Undecane

ChemComp-9PE:
(1R)-2-{[(S)-(2-aminoethoxy)(hydroxy)phosphoryl]oxy}-1-[(heptanoyloxy)methyl]ethyl octadecanoate / phospholipid*YM

ChemComp-LQ7:
N-(3-aminopropyl)-2-[(3-methylphenyl)methoxy]-N-[(thiophen-2-yl)methyl]benzamide

ChemComp-T14:
3-{7-(trifluoromethyl)-5-[2-(trifluoromethyl)phenyl]-1H-benzimidazol-2-yl}-1-oxa-2-azaspiro[4.5]dec-2-ene

ChemComp-CA:
CALCIUM ION / Calcium

Source
  • parus major (Great Tit)
KeywordsAmino Acid Sequence / Animals / Birds / Calcium / Cold Temperature / Cryoelectron Microscopy / HEK293 Cells / Humans / Models, Molecular / Protein Interaction Domains and Motifs / Protein Structure, Tertiary / Sequence Alignment / TRPM Cation Channels / TRPM8 protein, human / TRANSPORT PROTEIN / Ion Channel / TRPM8

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