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poly (ADP-ribose) polymerase 2, catalytic fragment in complex with ABT888

PDB Code 3KJD Target Class Poly ADP-ribose polymerase Target PARP2 + ABT888 Alias ADPRT2, ADPRTL2, ADPRTL3, pADPRT-2, PARP-2, PARP2 Disease Area/Function cancer Date Deposited Oct 22 2009 Authors T.KARLBERG, P.SCHUTZ, C.H.ARROWSMITH, H.BERGLUND, C.BOUNTRA, R.COLLINS, A.M.EDWARDS, S.FLODIN, A.FLORES, S.GRASLUND, M.HAMMARSTROM, A.JOHANSSON, I.JOHANSSON, A.KALLAS, T.KOTENYOVA, A.KOTZSCH, P.KRAULIS, T.K.NIELSEN, M.MOCHE, P.NORDLUND, T.NYMAN, C.PERSSON, A.K.ROOS, M.I.SIPONEN, A.G.THORSELL, L.TRESAUGUES, S.VAN DEN BERG, J.WEIGELT, M.WELIN, M.WISNIEWSKA, H.SCHULER Related Structure 3KCZ

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 (1). PAR is critically involved in genome organization, transcriptional regulation, and DNA repair (2). The human PARP family consists of 17 proteins that all contain a catalytic domain in the context of different domains conferring interactions with other proteins and subcellular localization (3). PARP-1 is triggered by DNA breaks and its activation initiates recruitment of the DNA repair machinery, and inhibiting this pathway is considered as a promising avenue for treatment of cancers in which mutations in the DNA damage response machinery are important (1). Several inhibitors have been developed that target the NAD+-binding site and inhibit the activity of PARP-1 and/or PARP-2.

PARP-2 (4) is the family member with greatest homology to PARP-1; PARP-2 and PARP-1 form functional heterodimers (5,6) but the two proteins may have overlapping functions (7). Here, the crystal structure of the catalytic domain of human PARP-2 is presented in complex with the NAD+-analogue inhibitor ABT-888 at 1.95Å resolution. ABT-888 has high (nanomolar) affinity towards PARP-1 and -2 (8). The structure consists of an N-terminal α-helical lobe and a C-terminal PARP domain similar to both PARP-1 and PARP-3. The PARP domain contains the PARP signature motif (9), a diphtheria toxin like fold (β-α-loop-β-α) on its inner surface, forming the NAD+ donor binding site located between the two subdomains. This structure may inform the rational design of inhibitors that are specific and selective within the PARP-1/ -2/ -3 clade.

References

  1. Hassa PO and Hottiger MO. (2008) The diverse biological roles of mammalian PARPs, a small but powerful family of poly-ADP-ribose polymerases. Front. Biosci. 13, 3046-3082. PubMed 17981777
  2. Schreiber V et al. (2006) Poly(ADP-ribose): novel functions for an old molecule. Nature Rev. Mol. Cell Biol. 7, 517-528. PubMed 16829982
  3. Amé JC et al. (2004) The PARP superfamily. Bioessays 26, 882-893. PubMed 15273990
  4. Amé JC et al. (1999) PARP-2, A novel mammalian DNA damage-dependent poly(ADP-ribose) polymerase. J Biol Chem 274, 17860-17868. PubMed 10364231
  5. Schreiber V et al. (2002) Poly(ADP-ribose) polymerase-2 (PARP-2) is required for efficient base excision DNA repair in association with PARP-1 and XRCC1. J Biol Chem 277, 23028-23036. PubMed 11948190
  6. Bryant HE et al. (2009) PARP is activated at stalled forks to mediate Mre11-dependent replication restart and recombination. EMBO J. 28, 2601-2615. PubMed 19629035
  7. Menissier de Murcia J et al. (2003) Functional interaction between PARP-1 and PARP-2 in chromosome stability and embryonic development in mouse. EMBO J. 22, 2255–2263. PubMed 12727891
  8. Penning TD et al. (2009) Discovery of the Poly(ADP-ribose) polymerase (PARP) inhibitor 2-[(R)-2-methylpyrrolidin-2-yl]-1H-benzimidazole-4-carboxamide (ABT-888) for the treatment of cancer. J Med Chem 52, 514-523. PubMed 19143569
  9. Otto H et al. (2005) In silico characterization of the family of PARP-like poly(ADPribosyl) transferases (pARTs). BMC Genomics 6, 139. PubMed 16202152