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- EMDB-20482: Human TRPM2 bound to 8-Br-cADPR and calcium -

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Basic information

Entry
Database: EMDB / ID: EMD-20482
TitleHuman TRPM2 bound to 8-Br-cADPR and calcium
Map data
Samplehuman TRPM2
  • Transient receptor potential cation channel subfamily M member 2
  • (ligand) x 2
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 / dendritic cell differentiation / cation transmembrane transport / regulation of filopodium assembly / sodium channel activity ...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 / dendritic cell differentiation / cation transmembrane transport / regulation of filopodium assembly / sodium channel activity / temperature homeostasis / TRP channels / calcium ion transmembrane import into cytosol / regulation of actin cytoskeleton reorganization / dendritic cell chemotaxis / calcium-release channel activity / calcium ion import across plasma membrane / ficolin-1-rich granule membrane / tertiary granule membrane / release of sequestered calcium ion into cytosol / calcium-mediated signaling using intracellular calcium source / specific granule membrane / cation channel activity / cellular response to calcium ion / calcium ion transmembrane transport / calcium channel activity / cell projection / calcium ion transport / cellular response to hydrogen peroxide / cytoplasmic vesicle membrane / lysosomal 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 / TRPM, SLOG domain / SLOG in TRPM / NUDIX hydrolase domain / Nudix hydrolase domain profile. / NUDIX hydrolase-like domain superfamily / Ion transport protein / Ion transport domain
Similarity search - Domain/homology
Transient receptor potential cation channel subfamily M member 2
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.7 Å
AuthorsDu J / Lu W / Huang Y
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)R01NS111031 United States
CitationJournal: Elife / Year: 2019
Title: Ligand recognition and gating mechanism through three ligand-binding sites of human TRPM2 channel.
Authors: Yihe Huang / Becca Roth / Wei Lü / Juan Du /
Abstract: TRPM2 is critically involved in diverse physiological processes including core temperature sensing, apoptosis, and immune response. TRPM2's activation by Ca and ADP ribose (ADPR), an NAD-metabolite ...TRPM2 is critically involved in diverse physiological processes including core temperature sensing, apoptosis, and immune response. TRPM2's activation by Ca and ADP ribose (ADPR), an NAD-metabolite produced under oxidative stress and neurodegenerative conditions, suggests a role in neurological disorders. We provide a central concept between triple-site ligand binding and the channel gating of human TRPM2. We show consecutive structural rearrangements and channel activation of TRPM2 induced by binding of ADPR in two indispensable locations, and the binding of Ca in the transmembrane domain. The 8-Br-cADPR-an antagonist of cADPR-binds only to the MHR1/2 domain and inhibits TRPM2 by stabilizing the channel in an apo-like conformation. We conclude that MHR1/2 acts as a orthostatic ligand-binding site for TRPM2. The NUDT9-H domain binds to a second ADPR to assist channel activation in vertebrates, but not necessary in invertebrates. Our work provides insights into the gating mechanism of human TRPM2 and its pharmacology.
History
DepositionJul 18, 2019-
Header (metadata) releaseJul 31, 2019-
Map releaseSep 25, 2019-
UpdateDec 18, 2019-
Current statusDec 18, 2019Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.009
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 0.009
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-6puu
  • Surface level: 0.009
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

Downloads & links

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Map

FileDownload / File: emd_20482.map.gz / Format: CCP4 / Size: 103 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.07 Å/pix.
x 300 pix.
= 322.2 Å
1.07 Å/pix.
x 300 pix.
= 322.2 Å
1.07 Å/pix.
x 300 pix.
= 322.2 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.074 Å
Density
Contour LevelBy AUTHOR: 0.009 / Movie #1: 0.009
Minimum - Maximum-0.0210351 - 0.04778512
Average (Standard dev.)0.00004284061 (±0.0024705718)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions300300300
Spacing300300300
CellA=B=C: 322.2 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.0741.0741.074
M x/y/z300300300
origin x/y/z0.0000.0000.000
length x/y/z322.200322.200322.200
α/β/γ90.00090.00090.000
start NX/NY/NZ1548552
NX/NY/NZ198170217
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS300300300
D min/max/mean-0.0210.0480.000

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Supplemental data

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Sample components

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Entire human TRPM2

EntireName: human TRPM2 / Number of Components: 4

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Component #1: protein, human TRPM2

ProteinName: human TRPM2 / Recombinant expression: No
SourceSpecies: Homo sapiens (human)
Source (engineered)Expression System: Homo sapiens (human)

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Component #2: protein, Transient receptor potential cation channel subfamily M ...

ProteinName: Transient receptor potential cation channel subfamily M member 2
Number of Copies: 4 / Recombinant expression: No
MassTheoretical: 172.280062 kDa
SourceSpecies: Homo sapiens (human)
Source (engineered)Expression System: Homo sapiens (human)

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Component #3: ligand, (2R,3R,4S,5R,13R,14S,15R,16R)-24-amino-18-bromo-3,4,14,15...

LigandName: (2R,3R,4S,5R,13R,14S,15R,16R)-24-amino-18-bromo-3,4,14,15-tetrahydroxy-7,9,11,25,26-pentaoxa-17,19,22-triaza-1-azonia-8,10-diphosphapentacyclo[18.3.1.1^2,5^.1^13,16^.0^17,21^]hexacosa-1(24) ...Name: (2R,3R,4S,5R,13R,14S,15R,16R)-24-amino-18-bromo-3,4,14,15-tetrahydroxy-7,9,11,25,26-pentaoxa-17,19,22-triaza-1-azonia-8,10-diphosphapentacyclo[18.3.1.1^2,5^.1^13,16^.0^17,21^]hexacosa-1(24),18,20,22-tetraene-8,10-diolate 8,10-dioxide
Number of Copies: 4 / Recombinant expression: No
MassTheoretical: 0.621204 kDa

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Component #4: ligand, CALCIUM ION

LigandName: CALCIUM IONCalcium / Number of Copies: 4 / Recombinant expression: No
MassTheoretical: 4.007805 MDa

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Experimental details

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Sample preparation

SpecimenSpecimen State: Particle / Method: cryo EM
Sample solutionpH: 8
Support filmunspecified
VitrificationCryogen Name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
ImagingMicroscope: FEI TITAN KRIOS
Electron gunElectron Source: FIELD EMISSION GUN / Accelerating Voltage: 300 kV / Electron Dose: 6.8 e/Å2 / Illumination Mode: FLOOD BEAM
LensCs: 2.7 mm / Imaging Mode: BRIGHT FIELD / Defocus: 1000.0 - 2500.0 nm
Specimen HolderModel: OTHER
CameraDetector: GATAN K2 SUMMIT (4k x 4k)

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Image processing

ProcessingMethod: single particle reconstruction / Number of Projections: 102259
3D reconstructionSoftware: RELION / Resolution: 3.7 Å / Resolution Method: FSC 0.143 CUT-OFF

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Atomic model buiding

Modeling #1Refinement space: REAL
Output model

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