6o77

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

Loading... Status: waiting for Mol* initialization Structural highlights 6o77 is a 4 chain structure with sequence from Parus major. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Electron Microscopy, Resolution 3.2Å Ligands: CA, Y01 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed 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. Structural insights into TRPM8 inhibition and desensitization.,Diver MM, Cheng Y, Julius D Science. 2019 Sep 27;365(6460):1434-1440. doi: 10.1126/science.aax6672. Epub 2019, Sep 5. PMID:31488702 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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