Crystal structure of the catalytic fragment of murine poly(ADP-ribose) polymerase-2
Open accessAbstract
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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PARP2 activity may influence NAD+ bioavailability.
“PARP2 activity may also influence NAD+ bioavailability25,26.”
From NAD+ metabolism and its roles in cellular processes during ageing (2021) · cites this paper as [26]
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NAD+ metabolism and its roles in cellular processes during ageing
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- Authors
- Oliver, A. W.
- Affiliations
- Institute of Cancer Research (GB)
- Corresponding author
- Oliver, A. W.
- ORCID
- Oliver, A. W.
- Venue
- Nucleic Acids Research
- Publisher
- Oxford University Press (OUP)
- Published
- 2004-01-21
- Volume
- 32
- Issue
- 2
- Pages
- 456-464
- ISSN
- 0305-1048 (ISSN-L)
- 1362-4962
- PMC
- PMC373339
- OpenAlex
- W1968625783
- Cited by
- 127
- References
- 43
- Citations by year
- 2026: 2 · 2025: 8 · 2024: 6 · 2023: 3 · 2022: 4 · 2021: 6 · 2020: 3 · 2019: 2 · 2018: 4 · 2017: 4 · 2016: 3 · 2015: 1 · 2014: 7 · 2013: 10 · 2012: 8
- FWCI
- 4.17
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Nucleic Acids Research (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Sussex Research Online (University of Sussex) (submittedVersion)
- HAL (submittedVersion)
- Figshare (submittedVersion, cc-by)
- Funders
- Cancer Research UK
- European Synchrotron Radiation Facility
- Topics
- Health Sciences › Medicine › Oncology › PARP inhibition in cancer therapy
- Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Keywords
- PARP1, catalytic fragment, crystal structure, PARP inhibitors, isoform selectivity, DNA damage response, PARP-1 inhibitors, rational drug design
- MeSH terms
- Poly(ADP-ribose) Polymerase Inhibitors, Amino Acid Sequence, Animals, Binding Sites, Catalysis, Cell Line, Chickens, Crystallization, DNA Damage, Enzyme Inhibitors, Isoenzymes, Models, Molecular, Molecular Sequence Data, Peptide Fragments, Poly(ADP-ribose) Polymerases, Protein Conformation, Substrate Specificity, Drug Design, Crystallography, X-Ray, Catalytic Domain, Mice
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