5NVH

Crystal structure of TNKS2 in complex with 2-[4-(piperidin-1-yl)phenyl]-3,4-dihydroquinazolin-4-one


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.60 Å
  • R-Value Free: 0.200 
  • R-Value Work: 0.178 
  • R-Value Observed: 0.179 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

2-Phenylquinazolinones as dual-activity tankyrase-kinase inhibitors.

Nkizinkiko, Y.Desantis, J.Koivunen, J.Haikarainen, T.Murthy, S.Sancineto, L.Massari, S.Ianni, F.Obaji, E.Loza, M.I.Pihlajaniemi, T.Brea, J.Tabarrini, O.Lehtio, L.

(2018) Sci Rep 8: 1680-1680

  • DOI: https://doi.org/10.1038/s41598-018-19872-3
  • Primary Citation of Related Structures:  
    5NSX, 5NT0, 5NT4, 5NUT, 5NVC, 5NVE, 5NVF, 5NVH, 5NWB, 5NWC, 5NWD, 5NWG, 5NXE, 5OWS, 5OWT

  • PubMed Abstract: 

    Tankyrases (TNKSs) are enzymes specialized in catalyzing poly-ADP-ribosylation of target proteins. Several studies have validated TNKSs as anti-cancer drug targets due to their regulatory role in Wnt/β-catenin pathway. Recently a lot of effort has been put into developing more potent and selective TNKS inhibitors and optimizing them towards anti-cancer agents. We noticed that some 2-phenylquinazolinones (2-PQs) reported as CDK9 inhibitors were similar to previously published TNKS inhibitors. In this study, we profiled this series of 2-PQs against TNKS and selected kinases that are involved in the Wnt/β-catenin pathway. We found that they were much more potent TNKS inhibitors than they were CDK9/kinase inhibitors. We evaluated the compound selectivity to tankyrases over the ARTD enzyme family and solved co-crystal structures of the compounds with TNKS2. Comparative structure-based studies of the catalytic domain of TNKS2 with selected CDK9 inhibitors and docking studies of the inhibitors with two kinases (CDK9 and Akt) revealed important structural features, which could explain the selectivity of the compounds towards either tankyrases or kinases. We also discovered a compound, which was able to inhibit tankyrases, CDK9 and Akt kinases with equal µM potency.


  • Organizational Affiliation

    Faculty of Biochemistry and Molecular Medicine & Biocenter Oulu, University of Oulu, Oulu, Finland.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Tankyrase-2A,
C [auth B]
191Homo sapiensMutation(s): 0 
Gene Names: TNKS2PARP5BTANK2TNKL
EC: 2.4.2.30
UniProt & NIH Common Fund Data Resources
Find proteins for Q9H2K2 (Homo sapiens)
Explore Q9H2K2 
Go to UniProtKB:  Q9H2K2
PHAROS:  Q9H2K2
GTEx:  ENSG00000107854 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ9H2K2
Sequence Annotations
Expand
  • Reference Sequence
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Tankyrase-2B [auth I],
D [auth J]
49Homo sapiensMutation(s): 0 
Gene Names: TNKS2PARP5BTANK2TNKL
EC: 2.4.2.30
UniProt & NIH Common Fund Data Resources
Find proteins for Q9H2K2 (Homo sapiens)
Explore Q9H2K2 
Go to UniProtKB:  Q9H2K2
PHAROS:  Q9H2K2
GTEx:  ENSG00000107854 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ9H2K2
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 5 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
9B2
Query on 9B2

Download Ideal Coordinates CCD File 
H [auth A],
N [auth B]
2-(4-piperidin-1-ylphenyl)-3~{H}-quinazolin-4-one
C19 H19 N3 O
CVOACSZXXZBJFG-UHFFFAOYSA-N
PEG
Query on PEG

Download Ideal Coordinates CCD File 
J [auth I]DI(HYDROXYETHYL)ETHER
C4 H10 O3
MTHSVFCYNBDYFN-UHFFFAOYSA-N
SO4
Query on SO4

Download Ideal Coordinates CCD File 
E [auth A],
F [auth A],
K [auth B],
L [auth B]
SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
GOL
Query on GOL

Download Ideal Coordinates CCD File 
I,
O [auth B]
GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
ZN
Query on ZN

Download Ideal Coordinates CCD File 
G [auth A],
M [auth B]
ZINC ION
Zn
PTFCDOFLOPIGGS-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
9B2 Binding MOAD:  5NVH IC50: 15 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.60 Å
  • R-Value Free: 0.200 
  • R-Value Work: 0.178 
  • R-Value Observed: 0.179 
  • Space Group: C 2 2 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 90.76α = 90
b = 98.25β = 90
c = 119.3γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
Biocenter OuluFinland--

Revision History  (Full details and data files)

  • Version 1.0: 2018-03-14
    Type: Initial release
  • Version 1.1: 2019-10-16
    Changes: Data collection
  • Version 1.2: 2024-01-17
    Changes: Data collection, Database references, Refinement description