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- PDB-6mix: Human TRPM2 ion channel in apo state -

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Basic information

Entry
Database: PDB / ID: 6mix
TitleHuman TRPM2 ion channel in apo state
ComponentsTransient receptor potential cation channel subfamily M member 2
KeywordsMEMBRANE PROTEIN / Channel / TRPM2 / TRP / ADPR / ADP-ribose / NUDT9H / NUDT9 / calcium / ion channel
Function / homology
Function and homology information


cellular response to purine-containing compound / response to purine-containing compound / mono-ADP-D-ribose binding / zinc ion transmembrane transport / cellular response to temperature stimulus / ligand-gated calcium channel activity / cation transmembrane transport / dendritic cell differentiation / metal ion transport / regulation of filopodium assembly ...cellular response to purine-containing compound / response to purine-containing compound / mono-ADP-D-ribose binding / zinc ion transmembrane transport / cellular response to temperature stimulus / ligand-gated calcium channel activity / cation transmembrane transport / dendritic cell differentiation / metal ion transport / regulation of filopodium assembly / temperature homeostasis / sodium channel activity / calcium ion transmembrane import into cytosol / TRP channels / calcium ion import across plasma membrane / regulation of actin cytoskeleton reorganization / dendritic cell chemotaxis / calcium-release channel activity / ficolin-1-rich granule membrane / tertiary granule membrane / release of sequestered calcium ion into cytosol / calcium-mediated signaling using intracellular calcium source / cation channel activity / specific granule membrane / cellular response to calcium ion / calcium channel activity / calcium ion transmembrane transport / cell projection / calcium ion transport / cellular response to hydrogen peroxide / lysosomal membrane / cytoplasmic vesicle membrane / perikaryon / protein homotetramerization / lysosome / Neutrophil degranulation / neutrophil degranulation / calcium ion binding / integral component of plasma membrane / plasma membrane
Similarity search - Function
Transient receptor potential cation channel subfamily M member 2 / SLOG in TRPM / TRPM, SLOG domain / NUDIX hydrolase domain / Nudix hydrolase domain profile. / NUDIX hydrolase-like domain superfamily / Ion transport domain / Ion transport protein
Similarity search - Domain/homology
Transient receptor potential cation channel subfamily M member 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.6 Å
AuthorsWang, L. / Fu, T.M. / Xia, S. / Wu, H.
CitationJournal: Science / Year: 2018
Title: Structures and gating mechanism of human TRPM2.
Authors: Longfei Wang / Tian-Min Fu / Yiming Zhou / Shiyu Xia / Anna Greka / Hao Wu /
Abstract: Transient receptor potential (TRP) melastatin 2 (TRPM2) is a cation channel associated with numerous diseases. It has a C-terminal NUDT9 homology (NUDT9H) domain responsible for binding adenosine ...Transient receptor potential (TRP) melastatin 2 (TRPM2) is a cation channel associated with numerous diseases. It has a C-terminal NUDT9 homology (NUDT9H) domain responsible for binding adenosine diphosphate (ADP)-ribose (ADPR), and both ADPR and calcium (Ca) are required for TRPM2 activation. Here we report cryo-electron microscopy structures of human TRPM2 alone, with ADPR, and with ADPR and Ca NUDT9H forms both intra- and intersubunit interactions with the N-terminal TRPM homology region (MHR1/2/3) in the apo state but undergoes conformational changes upon ADPR binding, resulting in rotation of MHR1/2 and disruption of the intersubunit interaction. The binding of Ca further engages transmembrane helices and the conserved TRP helix to cause conformational changes at the MHR arm and the lower gating pore to potentiate channel opening. These findings explain the molecular mechanism of concerted TRPM2 gating by ADPR and Ca and provide insights into the gating mechanism of other TRP channels.
History
DepositionSep 20, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 12, 2018Provider: repository / Type: Initial release
Revision 1.1Jan 2, 2019Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation_author.identifier_ORCID

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Structure visualization

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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


Theoretical massNumber of molelcules
Total (without water)685,6654
Polymers685,6654
Non-polymers00
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: equilibrium centrifugation
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area27040 Å2
ΔGint-186 kcal/mol
Surface area252840 Å2

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Components

#1: Protein
Transient receptor potential cation channel subfamily M member 2 / Estrogen-responsive element-associated gene 1 protein / Long transient receptor potential channel 2 ...Estrogen-responsive element-associated gene 1 protein / Long transient receptor potential channel 2 / LTrpC2 / Transient receptor potential channel 7 / TrpC7 / Transient receptor potential melastatin 2


Mass: 171416.188 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TRPM2, EREG1, KNP3, LTRPC2, TRPC7 / Production host: Homo sapiens (human) / References: UniProt: O94759

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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: Human TRPM2 ion channel / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.4
SpecimenConc.: 1 mg/ml / Embedding 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
Image recordingElectron dose: 70.12 e/Å2 / Detector mode: COUNTING / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.14_3260: / Classification: refinement
CTF correctionType: NONE
3D reconstructionResolution: 3.6 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 34477 / Symmetry type: POINT

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