5AEH

Crystal structure of human tankyrase 2 in complex with OD332

Summary for 5AEH

• Entry DOI: 10.2210/pdb5aeh/pdb
• Descriptor: TANKYRASE-2, N-{4-[(2-chlorophenyl)(pyrimidin-4-yl)carbamoyl]phenyl}-4-methoxybenzamide, ZINC ION, ... (4 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: 55648.14

Authors

Ignatev, A.,Lehtio, L. (deposition date: 2015-08-31, release date: 2016-01-13, Last modification date: 2024-01-10)

Primary citation

Haikarainen, T.,Waaler, J.,Ignatev, A.,Nkizinkiko, Y.,Venkannagari, H.,Obaji, E.,Krauss, S.,Lehtio, L.
Development and Structural Analysis of Adenosine Site Binding Tankyrase Inhibitors.
Bioorg.Med.Chem.Lett., 26:328-, 2016

PubMed Abstract: Tankyrases 1 and 2, the specialized members of the ARTD protein family, are druggable biotargets whose inhibition may have therapeutic potential against cancer, metabolic disease, fibrotic disease, fibrotic wound healing and HSV viral infections. We have previously identified a novel tankyrase inhibitor scaffold, JW55, and showed that it reduces mouse colon adenoma formation in vivo. Here we expanded the scaffold and profiled the selectivity of the compounds against a panel of human ARTDs. The scaffold also enables a fine modulation of selectivity towards either tankyrase 1 or tankyrase 2. In order to get insight about the binding mode of the inhibitors, we solved crystal structures of the compounds in complex with tankyrase 2. The compounds bind to the adenosine pocket of the catalytic domain and cause changes in the protein structure that are modulated by the chemical modifications of the compounds. The structural analysis allows further rational development of this compound class as a potent and selective tankyrase inhibitor.

PubMed: 26706174
DOI: 10.1016/J.BMCL.2015.12.018

Experimental method

X-RAY DIFFRACTION (1.85 Å)