Research Article

Structural insights into TRPM8 inhibition and desensitization

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Science  27 Sep 2019:
Vol. 365, Issue 6460, pp. 1434-1440
DOI: 10.1126/science.aax6672

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Responding to the cold

Mint tastes cool because the active component, menthol, activates the receptor and calcium channel TRPM8, which also responds to cold temperatures. Previous structures have revealed the architecture of TRPM8 and how it binds ligands but not its gating mechanism. Diver et al. determined structures of avian TRPM8 in ligand-free, antagonist-bound, and calcium-bound states using cryo–electron microscopy at resolutions between 3.0 and 3.6 angstroms. They observed a closed state in the presence of antagonist and that large conformational changes are required to form the desensitized state in the presence of calcium. Understanding how ligands affect channel gating may facilitate drug design.

Science, this issue p. 1434

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.

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