4UX4

Crystal structure of human tankyrase 2 in complex with 1-methyl-7-(4- methylphenyl)-5-oxo-5,6-dihydro-1,6-naphthyridin-1-ium


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.80 Å
  • R-Value Free: 0.198 
  • R-Value Work: 0.162 
  • R-Value Observed: 0.164 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Structure-Based Design, Synthesis and Evaluation in Vitro of Arylnaphthyridinones, Arylpyridopyrimidinones and Their Tetrahydro Derivatives as Inhibitors of the Tankyrases.

Kumpan, K.Nathubhai, A.Zhang, C.Wood, P.J.Lloyd, M.D.Thompson, A.S.Haikarainen, T.Lehtio, L.Threadgill, M.D.

(2015) Bioorg Med Chem 23: 3013

  • DOI: https://doi.org/10.1016/j.bmc.2015.05.005
  • Primary Citation of Related Structures:  
    4UX4, 4W5I

  • PubMed Abstract: 

    The tankyrases are members of the PARP superfamily; they poly(ADP-ribosyl)ate their target proteins using NAD(+) as a source of electrophilic ADP-ribosyl units. The three principal protein substrates of the tankyrases (TRF1, NuMA and axin) are involved in replication of cancer cells; thus inhibitors of the tankyrases may have anticancer activity. Using structure-based drug design and by analogy with known 3-arylisoquinolin-1-one and 2-arylquinazolin-4-one inhibitors, series of arylnaphthyridinones, arylpyridinopyrimidinones and their tetrahydro-derivatives were synthesised and evaluated in vitro. 7-Aryl-1,6-naphthyridin-5-ones, 3-aryl-2,6-naphthyridin-1-ones and 3-aryl-2,7-naphthyridin-1-ones were prepared by acid-catalysed cyclisation of the corresponding arylethynylpyridinenitriles or reaction of bromopyridinecarboxylic acids with β-diketones, followed by treatment with NH3. The 7-aryl-1,6-naphthyridin-5-ones were methylated at 1-N and reduced to 7-aryl-1-methyl-1,2,3,4-tetrahydro-1,6-naphthyridin-5-ones. Cu-catalysed reaction of benzamidines with bromopyridinecarboxylic acids furnished 2-arylpyrido[2,3-d]pyrimidin-4-ones. Condensation of benzamidines with methyl 1-benzyl-4-oxopiperidine-3-carboxylate and deprotection gave 2-aryl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ones, aza analogues of the known inhibitor XAV939. Introduction of the ring-N in the arylnaphthyridinones and the arylpyridopyrimidinones caused >1000-fold loss in activity, compared with their carbocyclic isoquinolinone and quinazolinone analogues. However, the 7-aryl-1-methyl-1,2,3,4-tetrahydro-1,6-naphthyridin-5-ones showed excellent inhibition of the tankyrases, with some examples having IC50=2nM. One compound (7-(4-bromophenyl)-1-methyl-1,2,3,4-tetrahydro-1,6-naphthyridin-5-one) showed 70-fold selectivity for inhibition of tankyrase-2 versus tankyrase-1. The mode of binding was explored through crystal structures of inhibitors in complex with tankyrase-2.


  • 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
E9L
Query on E9L

Download Ideal Coordinates CCD File 
C [auth A],
H [auth B]
(1S)-1-methyl-7-(4-methylphenyl)-5-oxo-1,5-dihydro-1,6-naphthyridin-1-ium
C16 H15 N2 O
GDYXASJFPBVBDV-UHFFFAOYSA-O
SO4
Query on SO4

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

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

Download Ideal Coordinates CCD File 
D [auth A],
I [auth B]
ZINC ION
Zn
PTFCDOFLOPIGGS-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.80 Å
  • R-Value Free: 0.198 
  • R-Value Work: 0.162 
  • R-Value Observed: 0.164 
  • Space Group: C 2 2 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 91.56α = 90
b = 97.89β = 90
c = 118.47γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
XDSdata reduction
XSCALEdata scaling

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2015-06-10
    Type: Initial release
  • Version 1.1: 2015-06-17
    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