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Human poly(ADP-ribose) polymerase 3, catalytic fragment in complex with an inhibitor PJ34

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PDB Code 3CE0 Target Class Poly ADP-ribose polymerase Target PARP3 Alias ADPRT3, ADPRTL2, ADPRTL3, hPARP-3, IRT1, pADPRT-3, PARP3 Disease Area/Function cancer Date Deposited Feb 28 2008 Authors LEHTIO, L., KARLBERG, T., ARROWSMITH, C., BERGLUND, H., BOUNTRA, C., BUSAM, R., COLLINS, R., DAHLGREN, L.G., EDWARDS, A., FLODIN, S., FLORES, A., GRASLUND, S., HAMMARSTROM, M., HERMAN, M.D., JOHANSSON, A., JOHANSSON, I., KALLAS, A., KOTENYOVA, T., MOCHE, M., NILSSON, M.E., NORDLUND, P., NYMAN, T., PERSSON, C., SAGEMARK, J., SVENSSON, L., THORSELL, A.G., TRESAUGUES, L., VAN DEN BERG, S., WELIN, M., WEIGELT, J. Related Structure 3FHB, 3C49, 3C4H

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 activity of the founding PARP-enzyme, 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-3 is a newly discovered member of the PARP family that has been shown to be a nuclear enzyme localized to polycomb group bodies and/or the centriole in close vicinity of PARP-1. Here, the crystal structure of the catalytic PARP-3 domain is presented in complex with a PARP-inhibitor PJ34 at 2.8 Å resolution.

Related structure: 2PA9 (SGC #400).

References

  1. Augustin, A. et al., (2003). PARP-3 localizes preferentially to the daughter centriole and interferes with the G1/S cell cycle progression. J. Cell Science 116, 1551-1562
  2. Bryant, HE. et al., (2005). Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature 434, 913-917.
  3. Rouleau, M. et al., (2007). PARP3 associates with polycomb group bodies and with components of the DNA damage repair machinery. J. Cell. Biochem. 100, 385-401.
  4. Schreiber, V. et al., (2006). Poly(ADP-ribose): novel functions for an old molecule. Nature Rev. Mol. Cell Biol. 7, 517-528.
  5. Jagtap, P. et al. (2002). Novel phenanthridinone inhibitors of poly(adenosine 5′-diphosphate-ribose) synthetase: potent cytoprotective and antishock agents. Crit. Care Med. 30, 1071–1082.