- Structural basis for inhibitor specificity in human poly(ADP-ribose) polymerase-3.
Structural basis for inhibitor specificity in human poly(ADP-ribose) polymerase-3.
Journal of medicinal chemistry (2009-04-10)
Lari Lehtiö, Ann-Sofie Jemth, Ruairi Collins, Olga Loseva, Andreas Johansson, Natalia Markova, Martin Hammarström, Alex Flores, Lovisa Holmberg-Schiavone, Johan Weigelt, Thomas Helleday, Herwig Schüler, Tobias Karlberg
PMID19354255
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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