6O72

Structure of the TRPM8 cold receptor by single particle electron cryo-microscopy, TC-I 2014-bound state

Summary for 6O72

• Entry DOI: 10.2210/pdb6o72/pdb
• Related: 6O6A 6O6R 6O77
• EMDB information: 0631 0636 0638 0639
• Descriptor: Transient receptor potential cation channel subfamily M member 8, CHOLESTEROL HEMISUCCINATE, UNDECANE, ... (6 entities in total)
• Functional Keywords: transport protein, ion channel, trpm8
• Biological source: Parus major (Great Tit)
• Total number of polymer chains: 4
• Total formula weight: 515585.20

Authors

Diver, M.M.,Cheng, Y.,Julius, D. (deposition date: 2019-03-07, release date: 2019-09-18, Last modification date: 2024-03-20)

Primary citation

Diver, M.M.,Cheng, Y.,Julius, D.
Structural insights into TRPM8 inhibition and desensitization.
Science, 365:1434-1440, 2019

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 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.

PubMed: 31488702
DOI: 10.1126/science.aax6672

Experimental method

ELECTRON MICROSCOPY (3 Å)