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Human Poly(ADP-Ribose) Polymerase15

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PDB Code 3BLJ Target Class Poly ADP-ribose polymerase Target PARP15 Alias BAL3, FLJ40196, FLJ40597, MGC126750, MGC126752, PARP15 Disease Area/Function cancer Date Deposited Dec 11 2007 Authors T.KARLBERG, L.LEHTIO, C.H.ARROWSMITH, H.BERGLUND, R.D.BUSAM, R.COLLINS, L.G.DAHLGREN, A.EDWARDS, S.FLODIN, A.FLORES, S.GRASLUND, M.HAMMARSTROM, I.JOHANSSON, A.KALLAS, T.KOTENYOVA, M.MOCHE, M.E.NILSSON, P.NORDLUND, T.NYMAN, C.PERSSON, J.SAGEMARK, L.SVENSSON, A.G.THORSELL, L.TRESAUGUES, S.VAN DEN BERG, M.WELIN, J.WEIGELT Related Structure 3GEY, 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. The PARP family consists of 17 members that all contain a catalytic PARP domain and additional specificity domains. PAR has been shown to be linked to transcriptional regulation, genome organization and DNA-repair. The founding member, PARP-1 is triggered by DNA 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/or PARP-2) and are effective against inflammation, neurodegenerative and vascular diseases. More importantly, several PARP-inhibitors that are in clinical trials are shown to enhance the activity of anti-proliferative agents in cancer therapy and are specifically shown to be efficient in killing tumor cells that lack the tumor suppressor BRCA2.

PARP-15 or BAL-3 (B-aggressive lymphoma) belongs to the sub-class of MACRO-PARPs. In addition to a catalytic PARP domain these proteins have one to three MACRO-domains in their N-terminal part. MACRO-PARPs are thought to be transcription cofactors. Here, the crystal structure of the catalytic PARP domain is presented at 2.2 Å resolution. In PARP-15 the catalytic domain is smaller than in other PARPs e.g. PARP-1 and -3 and an α-helical regulatory domain is missing in the presented structure. However, in PARP-15 the catalytic glutamate has been replaced by a leucine. The protein’s fold is comprised of two central β-sheets consisting of five and four strands. The β-sheets are surrounded by α-helices and loops.

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. Diefenbach, J. and Bürkle, A. (2005). Introduction to Poly(ADP-ribose) metabolism. Cell Mol. Life. Sci. 62, 721-730.