Please contact us for any questions or request for reagents for this structure.

Human Poly(ADP-ribose) polymerase 15, catalytic fragment in complex with an inhibitor PJ34

PDB Code 3GEY Target Class Poly ADP-ribose polymerase Target PARP15 + PJ34 Alias BAL3, FLJ40196, FLJ40597, MGC126750, MGC126752, PARP15 Disease Area/Function cancer Date Deposited Feb 26 2009 Authors T.KARLBERG, M.I.SIPONEN, C.H.ARROWSMITH, H.BERGLUND, C.BOUNTRA, R.COLLINS, A.M.EDWARDS, S.FLODIN, A.FLORES, S.GRASLUND, M.HAMMARSTROM, A.JOHANSSON, I.JOHANSSON, T.KOTENYOVA, M.MOCHE, P.NORDLUND, T.NYMAN, C.PERSSON, J.SAGEMARK, P.SCHUTZ, A.G.THORSELL, L.TRESAUGUES, S.VAN DEN BERG, J.WEIGELT, M.WELIN, M.WISNIEWSKA, H.SCHULER Related Structure 3BLJ, 3KH6

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 (1,2). 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. Several 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. Less is known about other members of the PARP family, but several of them are believed not to catalyze mono- and not poly-ADP-ribosylation reactions (3).

PARP-15 or BAL-3 (B-aggressive lymphoma) belongs to the sub-class of macro-PARPs, including also PARP-9 and PARP-14. In addition to a catalytic PARP domain these proteins have one to three MACRO-domains in their N-terminal part (4,5). Macro-PARPs are thought to be transcription cofactors (4). We have previously determined the structure of human PARP-15 without any ligands (PDB: 3BLJ). Here, the crystal structure of the catalytic PARP domain in complex with the PARP inhibitor PJ34 is presented at 2.2 Ċ resolution.

References

  1. Schreiber V. et al., (2006). Poly(ADP-ribose): novel functions for an old molecule. Nature Rev. Mol. Cell Biol. 7, 517-528.
  2. 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.
  3. 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.
  4. Aguiar RC., Takeyama K., He C, Kreinbrink K and Shipp MA. (2005) B-aggressive lymphoma family proteins have unique domains that modulate transcription and exhibit poly(ADP-ribose) polymerase activity. J. Biol.Chem. 40, 33756-33765.
  5. Karras GI., Kustatscher G., Buhecha1 HR., Allen MD., Pugieux C., Sait F., Bycroft M. and Ladurner AG. (2005) The macro domain is an ADP-ribose binding module. EMBO J. 24, 1911-1920.