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Structural basis for inhibitor specificity in human poly(ADP-ribose) polymerase-3

Lehtiö, Lari ; Jemth, Ann-Sofie ; Collins, Ruairi ; Loseva, Olga ; Johansson, Andreas ; Markova, Natalia LU ; Hammarström, Martin ; Flores, Alex ; Holmberg-Schiavone, Lovisa and Weigelt, Johan , et al. (2009) In Journal of Medicinal Chemistry 52(9). p.11-3108
Abstract

Poly(ADP-ribose) polymerases (PARPs) activate DNA repair mechanisms upon stress- and cytotoxin-induced DNA damage, and inhibition of PARP activity is a lead in cancer drug therapy. We present a structural and functional analysis of the PARP domain of human PARP-3 in complex with several inhibitors. Of these, KU0058948 is the strongest inhibitor of PARP-3 activity. The presented crystal structures highlight key features for potent inhibitor binding and suggest routes for creating isoenzyme-specific PARP inhibitors.

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publishing date
type
Contribution to journal
publication status
published
keywords
Biocatalysis/drug effects, Crystallography, X-Ray, Enzyme Inhibitors/chemistry, Humans, Models, Molecular, Poly(ADP-ribose) Polymerase Inhibitors, Poly(ADP-ribose) Polymerases/chemistry, Protein Conformation, Substrate Specificity
in
Journal of Medicinal Chemistry
volume
52
issue
9
pages
4 pages
publisher
The American Chemical Society (ACS)
external identifiers
  • scopus:65649119760
  • pmid:19354255
ISSN
1520-4804
DOI
10.1021/jm900052j
language
English
LU publication?
no
id
3432a8fe-7dc9-4fdf-8ef0-516a5a2b4a75
date added to LUP
2024-11-21 18:03:04
date last changed
2025-03-28 16:26:13
@article{3432a8fe-7dc9-4fdf-8ef0-516a5a2b4a75,
  abstract     = {{<p>Poly(ADP-ribose) polymerases (PARPs) activate DNA repair mechanisms upon stress- and cytotoxin-induced DNA damage, and inhibition of PARP activity is a lead in cancer drug therapy. We present a structural and functional analysis of the PARP domain of human PARP-3 in complex with several inhibitors. Of these, KU0058948 is the strongest inhibitor of PARP-3 activity. The presented crystal structures highlight key features for potent inhibitor binding and suggest routes for creating isoenzyme-specific PARP inhibitors.</p>}},
  author       = {{Lehtiö, Lari and Jemth, Ann-Sofie and Collins, Ruairi and Loseva, Olga and Johansson, Andreas and Markova, Natalia and Hammarström, Martin and Flores, Alex and Holmberg-Schiavone, Lovisa and Weigelt, Johan and Helleday, Thomas and Schüler, Herwig and Karlberg, Tobias}},
  issn         = {{1520-4804}},
  keywords     = {{Biocatalysis/drug effects; Crystallography, X-Ray; Enzyme Inhibitors/chemistry; Humans; Models, Molecular; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases/chemistry; Protein Conformation; Substrate Specificity}},
  language     = {{eng}},
  month        = {{05}},
  number       = {{9}},
  pages        = {{11--3108}},
  publisher    = {{The American Chemical Society (ACS)}},
  series       = {{Journal of Medicinal Chemistry}},
  title        = {{Structural basis for inhibitor specificity in human poly(ADP-ribose) polymerase-3}},
  url          = {{http://dx.doi.org/10.1021/jm900052j}},
  doi          = {{10.1021/jm900052j}},
  volume       = {{52}},
  year         = {{2009}},
}