4UVV

Crystal structure of human tankyrase 2 in complex with 3-(4- chlorophenyl)-5-methyl-1,2-dihydroisoquinolin-1-one


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.90 Å
  • R-Value Free: 0.198 
  • R-Value Work: 0.166 
  • R-Value Observed: 0.168 

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Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Exploration of the Nicotinamide-Binding Site of the Tankyrases, Identifying 3-Arylisoquinolin-1-Ones as Potent and Selective Inhibitors in Vitro.

Paine, H.A.Nathubhai, A.Woon, E.C.Y.Sunderland, P.T.Wood, P.J.Mahon, M.F.Lloyd, M.D.Thompson, A.S.Haikarainen, T.Narwal, M.Lehtio, L.Threadgill, M.D.

(2015) Bioorg Med Chem 23: 5891

  • DOI: https://doi.org/10.1016/j.bmc.2015.06.061
  • Primary Citation of Related Structures:  
    4UVL, 4UVN, 4UVO, 4UVP, 4UVS, 4UVT, 4UVU, 4UVV, 4UVW, 4UVX, 4UVY, 4UVZ

  • PubMed Abstract: 

    Tankyrases-1 and -2 (TNKS-1 and TNKS-2) have three cellular roles which make them important targets in cancer. Using NAD(+) as a substrate, they poly(ADP-ribosyl)ate TRF1 (regulating lengths of telomeres), NuMA (facilitating mitosis) and axin (in wnt/β-catenin signalling). Using molecular modelling and the structure of the weak inhibitor 5-aminoiso quinolin-1-one, 3-aryl-5-substituted-isoquinolin-1-ones were designed as inhibitors to explore the structure-activity relationships (SARs) for binding and to define the shape of a hydrophobic cavity in the active site. 5-Amino-3-arylisoquinolinones were synthesised by Suzuki-Miyaura coupling of arylboronic acids to 3-bromo-1-methoxy-5-nitro-isoquinoline, reduction and O-demethylation. 3-Aryl-5-methylisoquinolin-1-ones, 3-aryl-5-fluoroisoquinolin-1-ones and 3-aryl-5-methoxyisoquinolin-1-ones were accessed by deprotonation of 3-substituted-N,N,2-trimethylbenzamides and quench with an appropriate benzonitrile. SAR around the isoquinolinone core showed that aryl was required at the 3-position, optimally with a para-substituent. Small meta-substituents were tolerated but groups in the ortho-positions reduced or abolished activity. This was not due to lack of coplanarity of the rings, as shown by the potency of 4,5-dimethyl-3-phenylisoquinolin-1-one. Methyl and methoxy were optimal at the 5-position. SAR was rationalised by modelling and by crystal structures of examples with TNKS-2. The 3-aryl unit was located in a large hydrophobic cavity and the para-substituents projected into a tunnel leading to the exterior. Potency against TNKS-1 paralleled potency against TNKS-2. Most inhibitors were highly selective for TNKSs over PARP-1 and PARP-2. A range of highly potent and selective inhibitors is now available for cellular studies.


  • Organizational Affiliation

    Medicinal Chemistry, Department of Pharmacy & Pharmacology, University of Bath, Claverton Down, Bath BA2 7AY, UK.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
TANKYRASE-2
A, B
240Homo sapiensMutation(s): 0 
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 4 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
W8L
Query on W8L

Download Ideal Coordinates CCD File 
C [auth A],
I [auth B]
3-(4-chlorophenyl)-5-methylisoquinolin-1(2H)-one
C16 H12 Cl N O
CWBRRAZUVHYFCO-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 
G [auth A],
H [auth A],
M [auth B]
GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
ZN
Query on ZN

Download Ideal Coordinates CCD File 
D [auth A],
J [auth B]
ZINC ION
Zn
PTFCDOFLOPIGGS-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
W8L Binding MOAD:  4UVV IC50: 32 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.90 Å
  • R-Value Free: 0.198 
  • R-Value Work: 0.166 
  • R-Value Observed: 0.168 
  • Space Group: C 2 2 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 91.23α = 90
b = 97.72β = 90
c = 117.81γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
XDSdata reduction
XSCALEdata scaling

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2015-07-29
    Type: Initial release
  • Version 1.1: 2015-09-16
    Changes: Database references
  • Version 1.2: 2019-01-30
    Changes: Data collection, Experimental preparation
  • Version 1.3: 2019-02-06
    Changes: Data collection, Experimental preparation