[English] 日本語

- PDB-8w25: Cryo-EM structure of human tankyrase 2 SAM-PARP filament bound to... -
+
Open data
-
Basic information
Entry | Database: PDB / ID: 8w25 | ||||||
---|---|---|---|---|---|---|---|
Title | Cryo-EM structure of human tankyrase 2 SAM-PARP filament bound to compound, TDI-2804 (focused refinement map). | ||||||
![]() | Maltose/maltodextrin-binding periplasmic protein,Poly [ADP-ribose] polymerase tankyrase-2 | ||||||
![]() | SIGNALING PROTEIN/INHIBITOR / NAD+ ADP-ribosyltransferase / WNT signaling / inhibitor / SIGNALING PROTEIN / SIGNALING PROTEIN-INHIBITOR complex | ||||||
Function / homology | ![]() 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 | ||||||
Biological species | ![]() | ||||||
Method | ELECTRON MICROSCOPY / helical reconstruction / cryo EM / Resolution: 2.42 Å | ||||||
![]() | Malone, B.F. / Zimmerman, J.L. / Dow, L.E. / Hite, R.K. | ||||||
Funding support | 1items
| ||||||
![]() | ![]() 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 |
|
-
Structure visualization
Structure viewer | Molecule: ![]() ![]() |
---|
-
Downloads & links
-
Download
PDBx/mmCIF format | ![]() | 156.6 KB | Display | ![]() |
---|---|---|---|---|
PDB format | ![]() | Display | ![]() | |
PDBx/mmJSON format | ![]() | Tree view | ![]() | |
Others | ![]() |
-Validation report
Summary document | ![]() | 1.2 MB | Display | ![]() |
---|---|---|---|---|
Full document | ![]() | 1.2 MB | Display | |
Data in XML | ![]() | 41.8 KB | Display | |
Data in CIF | ![]() | 60.1 KB | Display | |
Arichive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 43739MC ![]() 8w23C ![]() 8w27C ![]() 8w28C ![]() 8w2tC ![]() 8w2uC C: citing same article ( M: map data used to model this data |
---|---|
Similar structure data | Similarity search - Function & homology ![]() |
-
Links
-
Assembly
Deposited unit | ![]()
|
---|---|
1 |
|
-
Components
#1: Protein | Mass: 80614.008 Da / Num. of mol.: 2 Source method: isolated from a genetically manipulated source Details: TNKS2 SAM-PARP fused to a N-terminal twin-strep-MBP tag,TNKS2 SAM-PARP fused to a N-terminal twin-strep-MBP tag,TNKS2 SAM-PARP fused to a N-terminal twin-strep-MBP tag,TNKS2 SAM-PARP fused ...Details: TNKS2 SAM-PARP fused to a N-terminal twin-strep-MBP tag,TNKS2 SAM-PARP fused to a N-terminal twin-strep-MBP tag,TNKS2 SAM-PARP fused to a N-terminal twin-strep-MBP tag,TNKS2 SAM-PARP fused to a N-terminal twin-strep-MBP tag Source: (gene. exp.) ![]() ![]() ![]() References: UniProt: P0AEY0, UniProt: Q9H2K2, NAD+ ADP-ribosyltransferase, Transferases; Glycosyltransferases; Pentosyltransferases #2: Chemical | #3: Chemical | Mass: 506.552 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C30H26N4O4 / Feature type: SUBJECT OF INVESTIGATION #4: Water | ChemComp-HOH / | Has ligand of interest | Y | Has protein modification | N | |
---|
-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
---|---|
EM experiment | Aggregation state: FILAMENT / 3D reconstruction method: helical reconstruction |
-
Sample preparation
Component | Name: Tankyrase 2 SAM-PARP filament bound to compound TDI-2804. Type: COMPLEX Details: Focused refinement surrounding repeating unit of the helical filament. Entity ID: #1 / Source: RECOMBINANT | ||||||||||||||||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Molecular weight | Experimental value: NO | ||||||||||||||||||||||||||||||
Source (natural) | Organism: ![]() | ||||||||||||||||||||||||||||||
Source (recombinant) | Organism: ![]() ![]() | ||||||||||||||||||||||||||||||
Buffer solution | pH: 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 |
| ||||||||||||||||||||||||||||||
Specimen | Conc.: 1.3 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES | ||||||||||||||||||||||||||||||
Vitrification | Instrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 95 % / Chamber temperature: 283 K |
-
Electron microscopy imaging
Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |
---|---|
Microscopy | Model: TFS KRIOS |
Electron gun | Electron source: ![]() |
Electron lens | Mode: BRIGHT FIELD / Nominal magnification: 29000 X / Nominal defocus max: 3000 nm / Nominal defocus min: 800 nm / Cs: 2.7 mm |
Specimen holder | Cryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER |
Image recording | Electron dose: 55.7 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) |
-
Processing
EM software |
| |||||||||||||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | |||||||||||||||||||||||||||
Helical symmerty | Angular rotation/subunit: -52.4 ° / Axial rise/subunit: 13.6 Å / Axial symmetry: D1 | |||||||||||||||||||||||||||
3D reconstruction | Resolution: 2.42 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 1310954 / Algorithm: FOURIER SPACE / Symmetry type: HELICAL | |||||||||||||||||||||||||||
Atomic model building | PDB-ID: 8ALY Accession code: 8ALY / Source name: PDB / Type: experimental model |