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- PDB-8w27: Cryo-EM structure of human tankyrase 2 SAM-PARP filament bound to... -

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Basic information

Entry
Database: PDB / ID: 8w27
TitleCryo-EM structure of human tankyrase 2 SAM-PARP filament bound to compound, XAV (consensus map).
ComponentsMaltose/maltodextrin-binding periplasmic protein,Poly [ADP-ribose] polymerase tankyrase-2
KeywordsSIGNALING PROTEIN/INHIBITOR / NAD+ 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 / negative regulation of telomere maintenance via telomere lengthening / protein auto-ADP-ribosylation / protein localization to chromosome, telomeric region / NAD+-protein-aspartate ADP-ribosyltransferase activity / protein poly-ADP-ribosylation / NAD+-protein-glutamate ADP-ribosyltransferase activity / pericentriolar material ...XAV939 stabilizes AXIN / positive regulation of telomere capping / NAD+ ADP-ribosyltransferase / negative regulation of telomere maintenance via telomere lengthening / protein auto-ADP-ribosylation / protein localization to chromosome, telomeric region / NAD+-protein-aspartate ADP-ribosyltransferase activity / protein poly-ADP-ribosylation / NAD+-protein-glutamate ADP-ribosyltransferase activity / pericentriolar material / NAD+-protein mono-ADP-ribosyltransferase activity / NAD+ poly-ADP-ribosyltransferase activity / Transferases; Glycosyltransferases; Pentosyltransferases / carbohydrate transmembrane transporter activity / maltose binding / maltose transport / maltodextrin transmembrane transport / ATP-binding cassette (ABC) transporter complex, substrate-binding subunit-containing / positive regulation of telomere maintenance via telomerase / nucleotidyltransferase activity / TCF dependent signaling in response to WNT / Degradation of AXIN / Wnt signaling pathway / Regulation of PTEN stability and activity / protein polyubiquitination / positive regulation of canonical Wnt signaling pathway / nuclear envelope / outer membrane-bounded periplasmic space / chromosome, telomeric region / Ub-specific processing proteases / Golgi membrane / perinuclear region of cytoplasm / enzyme binding / metal ion binding / nucleus / cytosol / cytoplasm
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) / Maltose/Cyclodextrin ABC transporter, substrate-binding protein / Solute-binding family 1, conserved site / Bacterial extracellular solute-binding proteins, family 1 signature. / SAM domain profile. / Sterile alpha motif. ...Ankyrin repeat / Poly(ADP-ribose) polymerase catalytic domain / Poly(ADP-ribose) polymerase, catalytic domain / PARP catalytic domain profile. / SAM domain (Sterile alpha motif) / Maltose/Cyclodextrin ABC transporter, substrate-binding protein / Solute-binding family 1, conserved site / Bacterial extracellular solute-binding proteins, family 1 signature. / SAM domain profile. / Sterile alpha motif. / Sterile alpha motif domain / Bacterial extracellular solute-binding protein / Bacterial extracellular solute-binding protein / 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
Chem-XAV / Maltose/maltodextrin-binding periplasmic protein / Poly [ADP-ribose] polymerase tankyrase-2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / helical reconstruction / cryo EM / Resolution: 2.21 Å
AuthorsMalone, B.F. / Zimmerman, J.L. / Dow, L.E. / Hite, R.K.
Funding support1items
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 20, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 9, 2025Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Maltose/maltodextrin-binding periplasmic protein,Poly [ADP-ribose] polymerase tankyrase-2
B: Maltose/maltodextrin-binding periplasmic protein,Poly [ADP-ribose] polymerase tankyrase-2
C: Maltose/maltodextrin-binding periplasmic protein,Poly [ADP-ribose] polymerase tankyrase-2
D: Maltose/maltodextrin-binding periplasmic protein,Poly [ADP-ribose] polymerase tankyrase-2
E: Maltose/maltodextrin-binding periplasmic protein,Poly [ADP-ribose] polymerase tankyrase-2
F: Maltose/maltodextrin-binding periplasmic protein,Poly [ADP-ribose] polymerase tankyrase-2
G: Maltose/maltodextrin-binding periplasmic protein,Poly [ADP-ribose] polymerase tankyrase-2
H: Maltose/maltodextrin-binding periplasmic protein,Poly [ADP-ribose] polymerase tankyrase-2
I: Maltose/maltodextrin-binding periplasmic protein,Poly [ADP-ribose] polymerase tankyrase-2
J: Maltose/maltodextrin-binding periplasmic protein,Poly [ADP-ribose] polymerase tankyrase-2
L: Maltose/maltodextrin-binding periplasmic protein,Poly [ADP-ribose] polymerase tankyrase-2
M: Maltose/maltodextrin-binding periplasmic protein,Poly [ADP-ribose] polymerase tankyrase-2
N: Maltose/maltodextrin-binding periplasmic protein,Poly [ADP-ribose] polymerase tankyrase-2
O: Maltose/maltodextrin-binding periplasmic protein,Poly [ADP-ribose] polymerase tankyrase-2
P: Maltose/maltodextrin-binding periplasmic protein,Poly [ADP-ribose] polymerase tankyrase-2
Q: Maltose/maltodextrin-binding periplasmic protein,Poly [ADP-ribose] polymerase tankyrase-2
R: Maltose/maltodextrin-binding periplasmic protein,Poly [ADP-ribose] polymerase tankyrase-2
S: Maltose/maltodextrin-binding periplasmic protein,Poly [ADP-ribose] polymerase tankyrase-2
T: Maltose/maltodextrin-binding periplasmic protein,Poly [ADP-ribose] polymerase tankyrase-2
U: Maltose/maltodextrin-binding periplasmic protein,Poly [ADP-ribose] polymerase tankyrase-2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)1,619,83560
Polymers1,612,28020
Non-polymers7,55440
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

#1: Protein
Maltose/maltodextrin-binding periplasmic protein,Poly [ADP-ribose] polymerase tankyrase-2 / MMBP / Maltodextrin-binding protein / Maltose-binding protein / MBP / ADP-ribosyltransferase ...MMBP / Maltodextrin-binding protein / Maltose-binding protein / MBP / ADP-ribosyltransferase diphtheria toxin-like 6 / ARTD6 / Poly [ADP-ribose] polymerase 5B / Protein poly-ADP-ribosyltransferase tankyrase-2 / TNKS-2 / TRF1-interacting ankyrin-related ADP-ribose polymerase 2 / Tankyrase II / Tankyrase-2 / TANK2 / Tankyrase-like protein / Tankyrase-related protein


Mass: 80614.008 Da / Num. of mol.: 20
Source method: isolated from a genetically manipulated source
Details: Tankyrase 2 fused to N-terminal twin-strep,Tankyrase 2 fused to N-terminal twin-strep
Source: (gene. exp.) Homo sapiens (human) / Gene: malE, Z5632, ECs5017, TNKS2, PARP5B, TANK2, TNKL / Cell line (production host): Sf9 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P0AEY0, UniProt: Q9H2K2, NAD+ ADP-ribosyltransferase, Transferases; Glycosyltransferases; Pentosyltransferases
#2: Chemical
ChemComp-XAV / 2-[4-(trifluoromethyl)phenyl]-7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidin-4-ol


Mass: 312.310 Da / Num. of mol.: 20 / Source method: obtained synthetically / Formula: C14H11F3N2OS / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 20 / Source method: obtained synthetically / Formula: Zn
Has ligand of interestY
Has protein modificationN

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: FILAMENT / 3D reconstruction method: helical reconstruction

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Sample preparation

ComponentName: Tankyrase 2 SAM-PARP filament bound to compound XAV. / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm) / Cell: Sf9
Buffer solutionpH: 7.5
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.
Buffer component
IDConc.NameFormulaBuffer-ID
1500 mMSodium ChlorideNaCl1
220 mMHEPES1
35 % v/vGlycerol1
42 mM2-mercaptoethanol1
50.05 % v/vTween-201
SpecimenConc.: 1.3 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 95 % / Chamber temperature: 283 K

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal magnification: 29000 X / Nominal defocus max: 3000 nm / Nominal defocus min: 800 nm / Cs: 2.7 mm
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 55.7 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

EM software
IDNameCategory
1cryoSPARCparticle selection
2SerialEMimage acquisition
4cryoSPARCCTF correction
7UCSF ChimeraXmodel fitting
9PHENIXmodel refinement
10cryoSPARCinitial Euler assignment
11cryoSPARCfinal Euler assignment
13cryoSPARC3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Helical symmertyAngular rotation/subunit: -52.4 ° / Axial rise/subunit: 13.6 Å / Axial symmetry: D1
3D reconstructionResolution: 2.21 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 1443106 / Symmetry type: HELICAL
Atomic model buildingPDB-ID: 8ALY

8aly


Accession code: 8ALY / Source name: PDB / Type: experimental model

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