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- PDB-6mj2: Human TRPM2 ion channel in a calcium- and ADPR-bound state -

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Basic information

Entry
Database: PDB / ID: 6mj2
TitleHuman TRPM2 ion channel in a calcium- and ADPR-bound 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


mono-ADP-D-ribose binding / manganese ion transmembrane transporter activity / ligand-gated calcium channel activity / zinc ion transmembrane transport / dendritic cell differentiation / response to purine-containing compound / regulation of filopodium assembly / cellular response to temperature stimulus / dendritic cell chemotaxis / response to hydroperoxide ...mono-ADP-D-ribose binding / manganese ion transmembrane transporter activity / ligand-gated calcium channel activity / zinc ion transmembrane transport / dendritic cell differentiation / response to purine-containing compound / regulation of filopodium assembly / cellular response to temperature stimulus / dendritic cell chemotaxis / response to hydroperoxide / calcium ion transmembrane import into cytosol / TRP channels / temperature homeostasis / sodium channel activity / intracellularly gated calcium channel activity / tertiary granule membrane / calcium ion import across plasma membrane / ficolin-1-rich granule membrane / specific granule membrane / monoatomic cation channel activity / release of sequestered calcium ion into cytosol / cytoplasmic vesicle membrane / cellular response to calcium ion / cell projection / regulation of actin cytoskeleton organization / calcium ion transmembrane transport / calcium channel activity / cellular response to hydrogen peroxide / calcium ion transport / response to heat / protein homotetramerization / perikaryon / lysosome / lysosomal membrane / calcium ion binding / Neutrophil degranulation / plasma membrane
Similarity search - Function
TRPM, SLOG domain / : / SLOG in TRPM / Nudix hydrolase domain profile. / NUDIX hydrolase domain / 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: 6.36 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
Revision 1.2Oct 9, 2024Group: Data collection / Database references / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _em_admin.last_update

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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)685,8258
Polymers685,6654
Non-polymers1604
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: equilibrium centrifugation
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area23150 Å2
ΔGint-271 kcal/mol
Surface area260190 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
#2: Chemical
ChemComp-CA / CALCIUM ION


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

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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
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 FIELD
Image recordingElectron dose: 70.072 e/Å2 / 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: 6.36 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 14199 / Symmetry type: POINT

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