4AVW

Crystal structure of human tankyrase 2 in complex with TIQ-A

Summary for 4AVW

• Entry DOI: 10.2210/pdb4avw/pdb
• Related: 2Y0I 4AVU
• Descriptor: TANKYRASE-2, 4H-thieno[2,3-c]isoquinolin-5-one, ZINC ION, ... (7 entities in total)
• Functional Keywords: transferase, transferase inhibitor complex, protein-ligand complex, diphtheria toxin like fold, adp-ribosylation
• Biological source: HOMO SAPIENS (HUMAN)
• Total number of polymer chains: 2
• Total formula weight: 55913.51

Authors

Haikarainen, T.,Narwal, M.,Lehtio, L. (deposition date: 2012-05-29, release date: 2012-06-13, Last modification date: 2024-05-08)

Primary citation

Haikarainen, T.,Narwal, M.,Joensuu, P.,Lehtio, L.
Evaluation and Structural Basis for the Inhibition of Tankyrases by Parp Inhibitors
Acs Med.Chem.Lett., 5:18-, 2014

PubMed Abstract: Tankyrases, an enzyme subfamily of human poly(ADP-ribosyl)polymerases, are potential drug targets especially against cancer. We have evaluated inhibition of tankyrases by known PARP inhibitors and report five cocrystal structures of the most potent compounds in complex with human tankyrase 2. The inhibitors include the small general PARP inhibitors Phenanthridinone, PJ-34, and TIQ-A as well as the more advanced inhibitors EB-47 and rucaparib. The compounds anchor to the nicotinamide subsite of tankyrase 2. Crystal structures reveal flexibility of the ligand binding site with implications for drug development against tankyrases and other ADP-ribosyltransferases. EB-47 mimics the substrate NAD(+) and extends from the nicotinamide to the adenosine subsite. The clinical ARTD1 inhibitor candidate rucaparib was the most potent tankyrase inhibitor identified (24 and 14 nM for tankyrases), which indicates that inhibition of tankyrases would affect the cellular responses of this compound.

PubMed: 24900770
DOI: 10.1021/ML400292S

Experimental method

X-RAY DIFFRACTION (2.15 Å)