4UI4: Crystal Structure Of Human Tankyrase 2 In Complex With Ta-29

Citation:
Abstract
Tankyrases (TNKSs), members of the PARP (Poly(ADP-ribose)polymerases) superfamily of enzymes, have gained interest as therapeutic drug targets, especially as they are involved in the regulation of Wnt signalling. A series of 2-arylquinazolin-4-ones with varying substituents at the 8-position was synthesised. An 8-methyl group (compared to 8-H, 8-OMe, 8-OH), together with a 4'-hydrophobic or electron-withdrawing group, provided the most potency and selectivity towards TNKSs. Co-crystal structures of selected compounds with TNKS-2 revealed that the protein around the 8-position is more hydrophobic in TNKS-2 compared to PARP-1/2, rationalising the selectivity. The NAD+-binding site contains a hydrophobic cavity which accommodates the 2-aryl group; in TNKS-2, this has a tunnel to the exterior but the cavity is closed in PARP-1. 8-Methyl-2-(4-trifluoromethylphenyl)quinazolin-4-one was identified as a potent and selective inhibitor of TNKSs and Wnt signalling. This compound and analogues could serve as molecular probes to study proliferative signalling and for development of inhibitors of TNKSs as drugs.
PDB ID: 4UI4Download
MMDB ID: 138247
PDB Deposition Date: 2015/3/27
Updated in MMDB: 2016/05
Experimental Method:
x-ray diffraction
Resolution: 2.4  Å
Source Organism:
Similar Structures:
Biological Unit for 4UI4: dimeric; determined by author and by software (PISA)
Molecular Components in 4UI4
Label Count Molecule
Proteins (2 molecules)
1
Tankyrase-2(Gene symbol: TNKS2)
Molecule annotation
1
Tankyrase-2(Gene symbol: TNKS2)
Molecule annotation
Chemicals (4 molecules)
1
2
2
1
3
1
* Click molecule labels to explore molecular sequence information.

Citing MMDB
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