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Crystal structure of the catalytic fragment of murine poly(ADP-ribose) polymerase-2.
Nucleic Acids Res. 2004; 32(2):456-64.NA

Abstract

Poly(ADP-ribose) polymerase-1 (PARP-1) has become an important pharmacological target in the treatment of cancer due to its cellular role as a 'DNA-strand break sensor', which leads in part to resistance to some existing chemo- and radiological treatments. Inhibitors have now been developed which prevent PARP-1 from synthesizing poly(ADP-ribose) in response to DNA-breaks and potentiate the cytotoxicity of DNA damaging agents. However, with the recent discoveries of PARP-2, which has a similar DNA-damage dependent catalytic activity, and additional members containing the 'PARP catalytic' signature, the isoform selectivity and resultant pharmacological effects of existing inhibitors are brought into question. We present here the crystal structure of the catalytic fragment of murine PARP-2, at 2.8 A resolution, and compare this to the catalytic fragment of PARP-1, with an emphasis on providing a possible framework for rational drug design in order to develop future isoform-specific inhibitors.

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Authors+Show Affiliations

Oliver AW
Cancer Research UK DNA Repair Enzyme Group, Section of Structural Biology, The Institute of Cancer Research, Chester Beatty Laboratories, 237 Fulham Road, London SW3 6JB, UK.
Amé JC
No affiliation info available
Roe SM
No affiliation info available
Good V
No affiliation info available
de Murcia G
No affiliation info available
Pearl LH
No affiliation info available

MeSH

Amino Acid SequenceAnimalsBinding SitesCatalysisCatalytic DomainCell LineChickensCrystallizationCrystallography, X-RayDNA DamageDrug DesignEnzyme InhibitorsIsoenzymesMiceModels, MolecularMolecular Sequence DataPeptide FragmentsPoly(ADP-ribose) Polymerase InhibitorsPoly(ADP-ribose) PolymerasesProtein ConformationSubstrate Specificity

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

14739238

Citation

Oliver, Antony W., et al. "Crystal Structure of the Catalytic Fragment of Murine poly(ADP-ribose) Polymerase-2." Nucleic Acids Research, vol. 32, no. 2, 2004, pp. 456-64.
Oliver AW, Amé JC, Roe SM, et al. Crystal structure of the catalytic fragment of murine poly(ADP-ribose) polymerase-2. Nucleic Acids Res. 2004;32(2):456-64.
Oliver, A. W., Amé, J. C., Roe, S. M., Good, V., de Murcia, G., & Pearl, L. H. (2004). Crystal structure of the catalytic fragment of murine poly(ADP-ribose) polymerase-2. Nucleic Acids Research, 32(2), 456-64.
Oliver AW, et al. Crystal Structure of the Catalytic Fragment of Murine poly(ADP-ribose) Polymerase-2. Nucleic Acids Res. 2004;32(2):456-64. PubMed PMID: 14739238.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Crystal structure of the catalytic fragment of murine poly(ADP-ribose) polymerase-2. AU - Oliver,Antony W, AU - Amé,Jean-Christophe, AU - Roe,S Mark, AU - Good,Valerie, AU - de Murcia,Gilbert, AU - Pearl,Laurence H, Y1 - 2004/01/22/ PY - 2004/1/24/pubmed PY - 2004/4/22/medline PY - 2004/1/24/entrez SP - 456 EP - 64 JF - Nucleic acids research JO - Nucleic Acids Res VL - 32 IS - 2 N2 - Poly(ADP-ribose) polymerase-1 (PARP-1) has become an important pharmacological target in the treatment of cancer due to its cellular role as a 'DNA-strand break sensor', which leads in part to resistance to some existing chemo- and radiological treatments. Inhibitors have now been developed which prevent PARP-1 from synthesizing poly(ADP-ribose) in response to DNA-breaks and potentiate the cytotoxicity of DNA damaging agents. However, with the recent discoveries of PARP-2, which has a similar DNA-damage dependent catalytic activity, and additional members containing the 'PARP catalytic' signature, the isoform selectivity and resultant pharmacological effects of existing inhibitors are brought into question. We present here the crystal structure of the catalytic fragment of murine PARP-2, at 2.8 A resolution, and compare this to the catalytic fragment of PARP-1, with an emphasis on providing a possible framework for rational drug design in order to develop future isoform-specific inhibitors. SN - 1362-4962 UR - https://www.unboundmedicine.com/medline/citation/14739238/Crystal_structure_of_the_catalytic_fragment_of_murine_poly_ADP_ribose__polymerase_2_ DB - PRIME DP - Unbound Medicine ER -