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

Human Poly (ADP-ribose) Polymerase 14, catalytic domain in complex with an inhibitor 3-Aminobenzamide

PDB Code 3GOY Target Class Poly ADP-ribose polymerase Target PARP14 Alias BAL2, KIAA1268, PARP14 Disease Area/Function cancer Date Deposited Mar 20 2009 Authors T.KARLBERG, M.MOCHE, 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, P.NORDLUND, T.NYMAN, C.PERSSON, J.SAGEMARK, P.SCHUTZ, M.I.SIPONEN, A.G.THORSELL, L.TRESAUGUES, S.VAN DEN BERG, J.WEIGELT, M.WELIN, M.WISNIEWSKA, H.SCHULER

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). 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 to catalyze mono- and not poly-ADP-ribosylation reactions (2).

PARP-14, also known as BAL-2 (B-aggressive lymphoma) or CoaSt6 (Collaborator of Stat6), belongs to the sub-class of Macro-PARPs, including also PARP-9 (BAL-1) and PARP-15 (BAL-3). In addition to a catalytic PARP domain these proteins have one to three Macro domains in their N-terminal part (3,4). Interestingly, the Macro domains selectively bind ADP-ribose and O-acetyl ADP-ribose, i.e. metabolites of NAD (4,5). The role of PARP-14 in B-cell lymphomas is unclear, but may be linked to the role of PARP-14 in regulating key players in apoptosis (6). We have determined the crystal structure of the catalytic domain of human PARP-14 in complex with the inhibitor 3-aminobenzamide at 2.8 Ċ resolution.

References

  1. 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.
  2. 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.
  3. 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.
  4. 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.
  5. Egloff, M-P., Malet, H., Putics, A., Heinonen, M., Dutartre, H., Frangeul, A., Gruez, A., Campanacci, V., Cambillau, C., Ziebuhr, J., Ahola, T. and Canard, B. (2006) Structural and functional basis for ADP-ribose and poly(ADP-ribose) binding by viral macro domains. Journal of Virology 80, 8493-8502.
  6. Cho, S.H., Goenka, S., Henttinen, T., Gudapati, P., Reinikainen, A., Eischen, C.M., Lahesmaa, R. and Boothby, M. (2009) PARP-14, a member of the B aggressive lymphoma (BAL) family, transduces survival signals in primary B cells. Blood 113, 2416-2425.