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- PDB-6o6r: Structure of the TRPM8 cold receptor by single particle electron ... -

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Entry
Database: PDB / ID: 6o6r
TitleStructure of the TRPM8 cold receptor by single particle electron cryo-microscopy, AMTB-bound state
ComponentsTransient receptor potential cation channel subfamily M member 8
KeywordsTRANSPORT PROTEIN / Ion Channel / TRPM8
Biological speciesParus major (Great Tit)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.2 Å
AuthorsDiver, M.M. / Cheng, Y. / Julius, D.
Funding support United States, 4items
OrganizationGrant numberCountry
National Institutes of Health/National Human Genome Research InstituteR35NS105038 United States
National Institutes of Health/National Human Genome Research InstituteR01GM098672 United States
National Institutes of Health/National Human Genome Research InstituteS10OD020054 United States
National Institutes of Health/National Human Genome Research InstituteS10OD021741 United States
CitationJournal: 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.
Validation Report
SummaryFull reportAbout validation report
History
DepositionMar 7, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 18, 2019Provider: repository / Type: Initial release

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Assembly

Deposited unit
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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)515,29432
Polymers507,9594
Non-polymers7,33428
Water0
1


TypeNameSymmetry operationNumber
identity operation1_5551
Buried area38730 Å2
ΔGint-324 kcal/mol
Surface area146360 Å2

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Components

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Protein/peptide , 1 types, 4 molecules ABCD

#1: Protein/peptide
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)

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Non-polymers , 5 types, 28 molecules

#2: Chemical
ChemComp-Y01 / CHOLESTEROL HEMISUCCINATE


Mass: 486.726 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C31H50O4
#3: Chemical
ChemComp-UND / UNDECANE / LIPID FRAGMENT


Mass: 156.308 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C11H24 / Undecane
#4: Chemical
ChemComp-9PE / (1R)-2-{[(S)-(2-aminoethoxy)(hydroxy)phosphoryl]oxy}-1-[(heptanoyloxy)methyl]ethyl octadecanoate / 3-SN-PHOSPHATIDYLETHANOLAMINE


Mass: 593.773 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C30H60NO8P / Comment: phospholipid *YM
#5: Chemical
ChemComp-LQ7 / N-(3-aminopropyl)-2-[(3-methylphenyl)methoxy]-N-[(thiophen-2-yl)methyl]benzamide


Mass: 394.530 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C23H26N2O2S
#6: Chemical
ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: Na / Sodium

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: 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 solutionpH: 7.4
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportDetails: unspecified
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELDBright-field microscopy / Nominal magnification: 22500 X / Nominal defocus max: 2000 nm / Nominal defocus min: 600 nm
Image recordingElectron dose: 70 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C4 (4 fold cyclic)
3D reconstructionResolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 92836 / Symmetry type: POINT

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