National Institutes of Health/National Human Genome Research Institute (NIH/NHGRI)
R35NS105038
米国
National Institutes of Health/National Human Genome Research Institute (NIH/NHGRI)
R01GM098672
米国
National Institutes of Health/National Human Genome Research Institute (NIH/NHGRI)
S10OD020054
米国
National Institutes of Health/National Human Genome Research Institute (NIH/NHGRI)
S10OD021741
米国
引用
ジャーナル: Science / 年: 2019 タイトル: Structural insights into TRPM8 inhibition and desensitization. 著者: Melinda M Diver / Yifan Cheng / David Julius / 要旨: 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.