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Human Poly (ADP-ribose) Polymerase 10, catalytic domain in complex with an inhibitor 3-Aminobenzamide

PDB Code 3HKV Target Class Poly ADP-ribose polymerase Target PARP10 Alias FLJ14464, PARP10 Disease Area/Function cancer Date Deposited May 26 2009 Authors T.KARLBERG, M.MOCHE, C.H.ARROWSMITH, H.BERGLUND, C.BOUNTRA, R.COLLINS, A.M.ED WARDS, S.FLODIN, A.FLORES, S.GRASLUND, M.HAMMARSTROM, A.JOHANSSON, I.JOHANSSON, T.KOTENYOVA, A .KOTZSCH, T.K.NIELSEN, P.NORDLUND, T.NYMAN, C.PERSSON, A.K.ROOS, J.SAGEMARK, P.SCHUTZ, M .I.SIPONEN, A.G.THORSELL, L.TRESAUGUES, S.VAN DEN BERG, J.WEIGELT, M.WELIN, M.WISNIEWSKA, H.SCHULER

About this structure

Poly(ADP-ribose) polymerases (PARPs) are enzymes that use NAD+ as a substrate to add poly(ADP)ribose (PAR) to other proteins or themselves, leading to a changed three-dimensional and electrostatic surface of the modified proteins. PAR has been shown to be linked to transcriptional regulation, genome organization and DNA-repair. The human PARP family consists of 17 members that all contain a catalytic PARP domain and additional specificity domains (1). The founding member, PARP-1, is triggered by DNA strand breaks and its activation results in the recruitment of the DNA repair machinery thus initiating a cellular response to DNA-damage. PARP-specific inhibitors have been developed that target the NAD+-binding site and inhibit the activity of PARP-1 (and possibly other PARPs). These inhibitors are effective against inflammation, neurodegenerative and vascular diseases, and several are in clinical trials as cancer drugs. PARP-10 is a 1025-residue nuclear and cytosolic protein with a C-terminal consensus PARP domain that is also implicated in binding to the Myc protein (2 – 4). Although little is known about the substrate spectrum for PARP-10, Myc does not seem to be among them, and PARP-10 is capable of both histone modification and automodification (2). Intriguingly, PARP-10 catalyzes mono- and not poly-ADP-ribosylation reactions, a fact that has been attributed to the absence of an otherwise conserved glutamate residue in the active site (5). We have determined the crystal structure of the catalytic domain of human PARP-10 in complex with the inhibitor 3-aminobenzamide at 2.1 Å resolution.

References

  1. Hakmé A., Wong H-K, Dantzer F. and Schreiber V. (2008). The expanding field of poly(ADP-ribosyl)ation reactions. EMBO reports 11, 1094-1100.
  2. Yu M, Schreek S, Cerni C, Schamberger C et al, and Lüscher B (2005) PARP-10, a novel Myc-interacting protein with poly(ADP-ribose) polymerase activity, inhibits transformation. Oncogene 17, 1982-1993.
  3. Lesniewicz K, Lüscher-Firzlaff J, Poreba E, Fuchs P, Walsemann G, Wiche G and Lüscher B (2005) Overlap of the gene encoding the novel poly(ADP-ribose) polymerase Parp10 with the plectin 1 gene and common use of exon sequences. Genomics 86, 38-46.
  4. Chou HY, Chou HT and Lee SC (2006) CDK-dependent activation of poly(ADP-ribose) polymerase member 10 (PARP10). J. Biol. Chem. 281, 15201-15207.
  5. Kleine H, Poreba E, Lesniewicz K, Hassa PO, Hottiger MO, Litchfield DW, Shilton BH and Lüscher B (2008) Substrate-assisted catalysis by PARP10 limits its activity to mono-ADP-Ribosylation. Mol. Cell 32, 57-69.