3MHK

Human tankyrase 2 - catalytic PARP domain in complex with 2-(2-pyridyl)-7,8-dihydro-5h-thiino[4,3-d]pyrimidin-4-ol

Summary for 3MHK

• Entry DOI: 10.2210/pdb3mhk/pdb
• Related: 3KR7 3KR8 3MHJ
• Descriptor: Tankyrase-2, ZINC ION, 2-pyridin-2-yl-7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidin-4-ol, ... (5 entities in total)
• Functional Keywords: catalytic fragment, parp, structural genomics, structural genomics consortium, sgc, adp-ribosylation, ank repeat, chromosomal protein, glycosyltransferase, golgi apparatus, membrane, mrna transport, nad, nucleus, phosphorylation, protein transport, telomere, transferase, translocation, transport, wnt-signalling
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: Q9H2K2
• Total number of polymer chains: 1
• Total formula weight: 26070.86

Authors

Karlberg, T.,Schutz, P.,Arrowsmith, C.H.,Berglund, H.,Bountra, C.,Collins, R.,Edwards, A.M.,Flodin, S.,Flores, A.,Graslund, S.,Hammarstrom, M.,Johansson, I.,Kotenyova, T.,Markova, N.,Moche, M.,Nordlund, P.,Nyman, T.,Persson, C.,Siponen, M.I.,Svensson, L.,Thorsell, A.G.,Tresaugues, L.,Van Den Berg, S.,Weigelt, J.,Welin, M.,Wisniewska, M.,Schuler, H.,Structural Genomics Consortium (SGC) (deposition date: 2010-04-08, release date: 2010-05-05, Last modification date: 2023-11-01)

Primary citation

Wahlberg, E.,Karlberg, T.,Kouznetsova, E.,Markova, N.,Macchiarulo, A.,Thorsell, A.G.,Pol, E.,Frostell, A.,Ekblad, T.,Kull, B.,Robertson, G.M.,Pellicciari, R.,Schuler, H.,Weigelt, J.
Family-wide chemical profiling and structural analysis of PARP and tankyrase inhibitors
Nat.Biotechnol., 30:283-288, 2012

PubMed Abstract: Inhibitors of poly-ADP-ribose polymerase (PARP) family proteins are currently in clinical trials as cancer therapeutics, yet the specificity of many of these compounds is unknown. Here we evaluated a series of 185 small-molecule inhibitors, including research reagents and compounds being tested clinically, for the ability to bind to the catalytic domains of 13 of the 17 human PARP family members including the tankyrases, TNKS1 and TNKS2. Many of the best-known inhibitors, including TIQ-A, 6(5H)-phenanthridinone, olaparib, ABT-888 and rucaparib, bound to several PARP family members, suggesting that these molecules lack specificity and have promiscuous inhibitory activity. We also determined X-ray crystal structures for five TNKS2 ligand complexes and four PARP14 ligand complexes. In addition to showing that the majority of PARP inhibitors bind multiple targets, these results provide insight into the design of new inhibitors.

PubMed: 22343925
DOI: 10.1038/nbt.2121

Experimental method

X-RAY DIFFRACTION (2.3 Å)