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Science. 2019 Sep 27;365(6460):1434-1440. doi: 10.1126/science.aax6672. Epub 2019 Sep 5.

Structural insights into TRPM8 inhibition and desensitization.

Author information

1
Department of Physiology, University of California, San Francisco, San Francisco, CA 94143, USA.
2
Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94143, USA. yifan.cheng@ucsf.edu david.julius@ucsf.edu.
3
Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA 94143, USA.
4
Department of Physiology, University of California, San Francisco, San Francisco, CA 94143, USA. yifan.cheng@ucsf.edu david.julius@ucsf.edu.

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.

PMID:
31488702
DOI:
10.1126/science.aax6672

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