4UHG

Crystal structure of human tankyrase 2 in complex with TA-21

Summary for 4UHG

• Entry DOI: 10.2210/pdb4uhg/pdb
• Related: 4UFU 4UFY 4UI3 4UI4 4UI5 4UI6 4UI7 4UI8
• Descriptor: TANKYRASE-2, ZINC ION, SULFATE ION, ... (6 entities in total)
• Functional Keywords: transferase, protein-ligand complex, diphtheria toxin like fold, adp- ribosylation, transferase-transferase inhibitor complex
• Biological source: HOMO SAPIENS (HUMAN)
• Cellular location: Cytoplasm: Q9H2K2
• Total number of polymer chains: 2
• Total formula weight: 55679.23

Authors

Haikarainen, T.,Lehtio, L. (deposition date: 2015-03-24, release date: 2016-04-13, Last modification date: 2024-05-08)

Primary citation

Nathubhai, A.,Haikarainen, T.,Hayward, P.C.,Munoz-Descalzo, S.,Thompson, A.S.,Lloyd, M.D.,Lehtio, L.,Threadgill, M.D.
Structure-Activity Relationships of 2-Arylquinazolin-4-Ones as Highly Selective and Potent Inhibitors of the Tankyrases.
Eur.J.Med.Chem., 118:316-, 2016

PubMed 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.

PubMed: 27163581
DOI: 10.1016/J.EJMECH.2016.04.041

Experimental method

X-RAY DIFFRACTION (1.7 Å)