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- PDB-6drj: Structure of TRPM2 ion channel receptor by single particle electr... -

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Basic information

Entry
Database: PDB / ID: 6drj
TitleStructure of TRPM2 ion channel receptor by single particle electron cryo-microscopy, ADPR/Ca2+ bound state
ComponentsTransient receptor potential cation channel, subfamily M, member 2
KeywordsTRANSPORT PROTEIN
Function / homology
Function and homology information


TRP channels / ligand-gated monoatomic cation channel activity / Neutrophil degranulation / ADP-D-ribose binding / mono-ADP-D-ribose binding / ligand-gated calcium channel activity / calcium ion transmembrane transport / calcium channel activity / monoatomic ion channel activity / protein homotetramerization ...TRP channels / ligand-gated monoatomic cation channel activity / Neutrophil degranulation / ADP-D-ribose binding / mono-ADP-D-ribose binding / ligand-gated calcium channel activity / calcium ion transmembrane transport / calcium channel activity / monoatomic ion channel activity / protein homotetramerization / calcium ion binding / plasma membrane
Similarity search - Function
TRPM, SLOG domain / SLOG in TRPM / NUDIX hydrolase-like domain superfamily / Ion transport domain / Ion transport protein
Similarity search - Domain/homology
ADENOSINE-5-DIPHOSPHORIBOSE / Transient receptor potential cation channel subfamily M member 2 / :
Similarity search - Component
Biological speciesDanio rerio (zebrafish)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.3 Å
AuthorsDu, J. / Lu, W. / Huang, Y. / Winkler, P. / Sun, W.
CitationJournal: Nature / Year: 2018
Title: Architecture of the TRPM2 channel and its activation mechanism by ADP-ribose and calcium.
Authors: Yihe Huang / Paige A Winkler / Weinan Sun / Wei Lü / Juan Du /
Abstract: Transient receptor potential melastatin 2 (TRPM2) is a calcium-permeable, non-selective cation channel that has an essential role in diverse physiological processes such as core body temperature ...Transient receptor potential melastatin 2 (TRPM2) is a calcium-permeable, non-selective cation channel that has an essential role in diverse physiological processes such as core body temperature regulation, immune response and apoptosis. TRPM2 is polymodal and can be activated by a wide range of stimuli, including temperature, oxidative stress and NAD-related metabolites such as ADP-ribose (ADPR). Its activation results in both Ca entry across the plasma membrane and Ca release from lysosomes, and has been linked to diseases such as ischaemia-reperfusion injury, bipolar disorder and Alzheimer's disease. Here we report the cryo-electron microscopy structures of the zebrafish TRPM2 in the apo resting (closed) state and in the ADPR/Ca-bound active (open) state, in which the characteristic NUDT9-H domains hang underneath the MHR1/2 domain. We identify an ADPR-binding site located in the bi-lobed structure of the MHR1/2 domain. Our results provide an insight into the mechanism of activation of the TRPM channel family and define a framework for the development of therapeutic agents to treat neurodegenerative diseases and temperature-related pathological conditions.
History
DepositionJun 12, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 19, 2018Provider: repository / Type: Initial release
Revision 1.1Sep 26, 2018Group: Data collection / Structure summary / Category: struct / Item: _struct.title
Revision 1.2Oct 10, 2018Group: Data collection / Database references / Structure summary
Category: citation / entity
Item: _citation.journal_id_ISSN / _citation.journal_volume ..._citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title / _entity.formula_weight

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Assembly

Deposited unit
A: Transient receptor potential cation channel, subfamily M, member 2
B: Transient receptor potential cation channel, subfamily M, member 2
C: Transient receptor potential cation channel, subfamily M, member 2
D: Transient receptor potential cation channel, subfamily M, member 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)675,93112
Polymers673,5344
Non-polymers2,3988
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area21330 Å2
ΔGint-275 kcal/mol
Surface area250690 Å2

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Components

#1: Protein
Transient receptor potential cation channel, subfamily M, member 2


Mass: 168383.469 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Danio rerio (zebrafish) / Gene: trpm2 / Cell line (production host): HEK293 GnTI- / Production host: Homo sapiens (human) / References: UniProt: A0A0R4IN04, UniProt: A0A0R4IMY7*PLUS
#2: Chemical
ChemComp-APR / ADENOSINE-5-DIPHOSPHORIBOSE


Mass: 559.316 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C15H23N5O14P2
#3: Chemical
ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Ca

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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: Ion channel 1 / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Molecular weightValue: 0.5 MDa / Experimental value: YES
Source (natural)Organism: Danio rerio (zebrafish)
Source (recombinant)Organism: Mammalia (mammals)
Buffer solutionpH: 8
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
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: OTHER
Electron lensMode: BRIGHT FIELDBright-field microscopy
Image recordingElectron dose: 45 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

SoftwareName: PHENIX / Version: dev_3084: / Classification: refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 227007 / Symmetry type: POINT

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