|Entry||Database: PDB / ID: 6o77|
|Title||Structure of the TRPM8 cold receptor by single particle electron cryo-microscopy, calcium-bound state|
|Components||Transient receptor potential cation channel subfamily M member 8|
|Keywords||TRANSPORT PROTEIN / Ion Channel / TRPM8|
|Biological species||Parus major (Great Tit)|
|Method||ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.2 Å|
|Authors||Diver, M.M. / Cheng, Y. / Julius, D.|
|Funding support|| United States, 4items |
|Citation||Journal: Science / Year: 2019|
Title: Structural insights into TRPM8 inhibition and desensitization.
Authors: Melinda M Diver / Yifan Cheng / David Julius /
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 ...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.
SummaryFull reportAbout validation report
|Structure viewer||Molecule: |
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A: Transient receptor potential cation channel subfamily M member 8
B: Transient receptor potential cation channel subfamily M member 8
C: Transient receptor potential cation channel subfamily M member 8
D: Transient receptor potential cation channel subfamily M member 8
Mass: 126989.797 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Parus major (Great Tit) / Production host: Homo sapiens (human)
|Experiment||Method: ELECTRON MICROSCOPY|
|EM experiment||Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction|
|Component||Name: Transient receptor potential cation channel subfamily M member 8|
Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
|Source (natural)||Organism: Parus major (Great Tit)|
|Source (recombinant)||Organism: Homo sapiens (human)|
|Buffer solution||pH: 7.4|
|Specimen||Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES|
|Specimen support||Details: unspecified|
|Vitrification||Cryogen name: ETHANE|
-Electron microscopy imaging
Model: Titan Krios / Image courtesy: FEI Company
|Microscopy||Model: FEI TITAN KRIOS|
|Electron gun||Electron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM|
|Electron lens||Mode: BRIGHT FIELDBright-field microscopy / Nominal magnification: 22500 X / Nominal defocus max: 2000 nm / Nominal defocus min: 600 nm|
|Image recording||Electron dose: 70 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k)|
|CTF correction||Type: PHASE FLIPPING AND AMPLITUDE CORRECTION|
|Symmetry||Point symmetry: C4 (4 fold cyclic)|
|3D reconstruction||Resolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 42040 / Symmetry type: POINT|
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