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human Poly [ADP-ribose] polymerase 12

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PDB Code 2PQF Target Class Poly ADP-ribose polymerase Target PARP12 Alias FLJ22693, MST109, MSTP109, PARP-12, PARP12, ZC3H1, ZC3HDC1 Disease Area/Function cancer Date Deposited May 02 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, M.HOGBOM, I.JOHANSSON, A.KALLAS, T.KOTENYOVA, M.MOCHE, P.NORDLUND, T.NYMAN, C.PERSSON, J.SAGEMARK, M.SUNDSTROM, A.G.THORSELL, S.VAN DEN BERG, J.WEIGELT, L.HOLMBERG-SCHIAVONE, STRUCTURAL GENOMICS CONSORTIUM (SGC)

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-12 belongs to the CCCH-type zinc finger PARPs. Members of this subfamily have a similar domain organization comprising a zinc-finger domain, a WWE-domain and a PARP catalytic domain. Here, the crystal structure of the catalytic PARP domain is presented in complex with the NAD-analogue inhibitor 3-aminobenzoic acid (3-ABA) at 2.2 Ċ resolution. In PARP-12 the catalytic domain is smaller than in other PARPs e.g. PARP-1-3 and thus an α-helical regulatory domain is missing in the presented structure. Interaction between residues at the active site in PARP-12 and inhibitor is conserved. However, in PARP12 the catalytic glutamate has been replaced by an isoleucine. The presented structure will be important for development of specific/selective PARP inhibitors.

References

  1. 1. Schreiber, V. et al., (2006). Poly(ADP-ribose): novel functions for an old molecule. Nature Rev. Mol. Cell Biol. 7, 517-528.
  2. 2. Diefenbach, J. and Bürkle, A. (2005). Introduction to Poly(ADP-ribose) metabolism. Cell Mol. Life. Sci. 62, 721-730.