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- EMDB-43758: Cryo-EM structure of human tankyrase 2 SAM-PARP filament - apo st... -

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Basic information

Entry
Database: EMDB / ID: EMD-43758
TitleCryo-EM structure of human tankyrase 2 SAM-PARP filament - apo state (focused refinement map).
Map dataLocal resolution filtered map
Sample
  • Complex: Tankyrase 2 SAM-PARP filament - apo state
    • Protein or peptide: Poly [ADP-ribose] polymerase tankyrase-2
  • Ligand: ZINC ION
KeywordsNAD+ ADP-ribosyltransferase / WNT signaling / inhibitor / SIGNALING PROTEIN / SIGNALING PROTEIN-INHIBITOR complex
Function / homology
Function and homology information


XAV939 stabilizes AXIN / positive regulation of telomere capping / NAD+ ADP-ribosyltransferase / protein auto-ADP-ribosylation / negative regulation of telomere maintenance via telomere lengthening / protein localization to chromosome, telomeric region / NAD+-protein-aspartate ADP-ribosyltransferase activity / protein poly-ADP-ribosylation / NAD+-protein-glutamate ADP-ribosyltransferase activity / NAD+-protein mono-ADP-ribosyltransferase activity ...XAV939 stabilizes AXIN / positive regulation of telomere capping / NAD+ ADP-ribosyltransferase / protein auto-ADP-ribosylation / negative regulation of telomere maintenance via telomere lengthening / protein localization to chromosome, telomeric region / NAD+-protein-aspartate ADP-ribosyltransferase activity / protein poly-ADP-ribosylation / NAD+-protein-glutamate ADP-ribosyltransferase activity / NAD+-protein mono-ADP-ribosyltransferase activity / pericentriolar material / Transferases; Glycosyltransferases; Pentosyltransferases / NAD+ poly-ADP-ribosyltransferase activity / positive regulation of telomere maintenance via telomerase / nucleotidyltransferase activity / TCF dependent signaling in response to WNT / Degradation of AXIN / Regulation of PTEN stability and activity / Wnt signaling pathway / protein polyubiquitination / nuclear envelope / positive regulation of canonical Wnt signaling pathway / chromosome, telomeric region / Ub-specific processing proteases / Golgi membrane / perinuclear region of cytoplasm / enzyme binding / metal ion binding / nucleus / cytoplasm / cytosol
Similarity search - Function
Ankyrin repeat / Poly(ADP-ribose) polymerase catalytic domain / Poly(ADP-ribose) polymerase, catalytic domain / PARP catalytic domain profile. / SAM domain (Sterile alpha motif) / SAM domain profile. / Sterile alpha motif. / Sterile alpha motif domain / Sterile alpha motif/pointed domain superfamily / Ankyrin repeat ...Ankyrin repeat / Poly(ADP-ribose) polymerase catalytic domain / Poly(ADP-ribose) polymerase, catalytic domain / PARP catalytic domain profile. / SAM domain (Sterile alpha motif) / SAM domain profile. / Sterile alpha motif. / Sterile alpha motif domain / Sterile alpha motif/pointed domain superfamily / Ankyrin repeat / Ankyrin repeats (3 copies) / Ankyrin repeat profile. / Ankyrin repeat region circular profile. / ankyrin repeats / Ankyrin repeat / Ankyrin repeat-containing domain superfamily
Similarity search - Domain/homology
Poly [ADP-ribose] polymerase tankyrase-2
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodhelical reconstruction / cryo EM / Resolution: 2.52 Å
AuthorsMalone BF / Zimmerman JL / Dow LE / Hite RK
Funding support1 items
OrganizationGrant numberCountry
Not funded
CitationJournal: bioRxiv / Year: 2025
Title: A potent and selective TNKS2 inhibitor for tumor-selective WNT suppression.
Authors: Jill Zimmerman / Brandon F Malone / Efrat Finkin-Groner / Shan Sun / Rui Liang / Miguel Foronda / Emma M Schatoff / Elizabeth Granowsky / Sukanya Goswami / Alyna Katti / Benjamin Leach / ...Authors: Jill Zimmerman / Brandon F Malone / Efrat Finkin-Groner / Shan Sun / Rui Liang / Miguel Foronda / Emma M Schatoff / Elizabeth Granowsky / Sukanya Goswami / Alyna Katti / Benjamin Leach / Heather Alcorn / Tuomas Tammela / Yoshiyuki Fukase / Tanweer Khan / David J Huggins / John Ginn / Nigel Liverton / Richard K Hite / Lukas E Dow /
Abstract: Hyperactive WNT signaling is a potent cancer driver, but clinical translation of WNT inhibitors has been hampered by on-target toxicities. WNT signaling can be constrained through inhibition of the ...Hyperactive WNT signaling is a potent cancer driver, but clinical translation of WNT inhibitors has been hampered by on-target toxicities. WNT signaling can be constrained through inhibition of the PARP family enzymes Tankyrase 1 (TNKS1) and Tankyrase 2 (TNKS2), however, existing TNKS inhibitors suppress WNT signaling in both tumor and healthy tissues. In this study, we show that the loss of chromosome 8p that occurs in approximately half of advanced epithelial malignancies, creates a collateral vulnerability that enables tumor-selective inhibition of Tankyrase activity. 8p loss depletes expression of TNKS1 and creates a tumor-specific dependency on the functionally redundant TNKS2 protein. Through structure-guided drug design, we identify a first-in-class TNKS2-selective inhibitor that can drive selective WNT inhibition in TNKS1-deficient oncogenic cell and organoid models. This work demonstrates a targetable vulnerability in multiple cancer types, providing a new approach to potent and selective WNT-targeted therapies.
History
DepositionFeb 21, 2024-
Header (metadata) releaseJul 9, 2025-
Map releaseJul 9, 2025-
UpdateJul 9, 2025-
Current statusJul 9, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_43758.png

Downloads & links

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Map

FileDownload / File: emd_43758.map.gz / Format: CCP4 / Size: 216 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationLocal resolution filtered map
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.83 Å/pix.
x 384 pix.
= 317.184 Å		0.83 Å/pix.
x 384 pix.
= 317.184 Å		0.83 Å/pix.
x 384 pix.
= 317.184 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.826 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.05
Minimum - Maximum-0.39139804 - 0.5663237
Average (Standard dev.)0.000038325095 (±0.0052810046)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions384384384
Spacing384384384
CellA=B=C: 317.184 Å
α=β=γ: 90.0 °

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Supplemental data

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Additional map: Raw map

Fileemd_43758_additional_1.map
AnnotationRaw map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Additional map: B-factor sharpened map

Fileemd_43758_additional_2.map
AnnotationB-factor sharpened map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half map A

Fileemd_43758_half_map_1.map
AnnotationHalf map A
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half map B

Fileemd_43758_half_map_2.map
AnnotationHalf map B
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Tankyrase 2 SAM-PARP filament - apo state

EntireName: Tankyrase 2 SAM-PARP filament - apo state
Components
  • Complex: Tankyrase 2 SAM-PARP filament - apo state
    • Protein or peptide: Poly [ADP-ribose] polymerase tankyrase-2
  • Ligand: ZINC ION

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Supramolecule #1: Tankyrase 2 SAM-PARP filament - apo state

SupramoleculeName: Tankyrase 2 SAM-PARP filament - apo state / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Details: Focused refinement surrounding repeating unit of the helical filament.
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Poly [ADP-ribose] polymerase tankyrase-2

MacromoleculeName: Poly [ADP-ribose] polymerase tankyrase-2 / type: protein_or_peptide / ID: 1
Details: Tankyrase 2 SAM-PARP. Aligned sequence starting 'DFS...' should be numbered starting 875 to align with the uniprot numbering.
Number of copies: 2 / Enantiomer: LEVO / EC number: NAD+ ADP-ribosyltransferase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 35.65734 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: ELSSVVSSSG TEGASSLEKK EVPGVDFSIT QFVRNLGLEH LMDIFEREQI TLDVLVEMGH KELKEIGINA YGHRHKLIKG VERLISGQQ GLNPYLTLNT SGSGTILIDL SPDDKEFQSV EEEMQSTVRE HRDGGHAGGI FNRYNILKIQ KVCNKKLWER Y THRRKEVS ...String:
ELSSVVSSSG TEGASSLEKK EVPGVDFSIT QFVRNLGLEH LMDIFEREQI TLDVLVEMGH KELKEIGINA YGHRHKLIKG VERLISGQQ GLNPYLTLNT SGSGTILIDL SPDDKEFQSV EEEMQSTVRE HRDGGHAGGI FNRYNILKIQ KVCNKKLWER Y THRRKEVS EENHNHANER MLFHGSPFVN AIIHKGFDER HAYIGGMFGA GIYFAENSSK SNQYVYGIGG GTGCPVHKDR SC YICHRQL LFCRVTLGKS FLQFSAMKMA HSPPGHHSVT GRPSVNGLAL AEYVIYRGEQ AYPEYLITYQ IMRPEGMVDG

UniProtKB: Poly [ADP-ribose] polymerase tankyrase-2

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Macromolecule #2: ZINC ION

MacromoleculeName: ZINC ION / type: ligand / ID: 2 / Number of copies: 2 / Formula: ZN
Molecular weightTheoretical: 65.409 Da

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Experimental details

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Structure determination

Methodcryo EM
Processinghelical reconstruction
Aggregation statefilament

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Sample preparation

Concentration1.3 mg/mL
BufferpH: 7.5
Component:
ConcentrationFormulaName
500.0 millimolarNaClSodium Chloride
20.0 millimolarHEPES
5.0 % v/vGlycerol
2.0 millimolar2-mercaptoethanol
0.05 % v/vTween-20

Details: Sample was purified and concentrated in the above buffer but exchanged prior to vitrification to a low-salt (minimal) buffer composed of 20 millimolar HEPES pH 7.5. Sample buffer was ...Details: Sample was purified and concentrated in the above buffer but exchanged prior to vitrification to a low-salt (minimal) buffer composed of 20 millimolar HEPES pH 7.5. Sample buffer was exchanged on grid via manual side-blotting.
VitrificationCryogen name: ETHANE / Chamber humidity: 95 % / Chamber temperature: 283 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 55.7 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 3.0 µm / Nominal defocus min: 0.8 µm / Nominal magnification: 29000
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Final reconstructionApplied symmetry - Helical parameters - Δz: 13.6 Å
Applied symmetry - Helical parameters - Δ&Phi: -52.4 °
Applied symmetry - Helical parameters - Axial symmetry: D1 (2x1 fold dihedral)
Resolution.type: BY AUTHOR / Resolution: 2.52 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 412596
CTF correctionSoftware - Name: cryoSPARC / Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: INSILICO MODEL / In silico model: Ab-initio reconstruction in cryosparc
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial modelPDB ID:

8aly


Chain - Source name: PDB / Chain - Initial model type: experimental model
Output model

PDB-8w2t:
Cryo-EM structure of human tankyrase 2 SAM-PARP filament - apo state (focused refinement map).

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