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

J Med Chem. 2009 May 14;52(9):3108-11. doi: 10.1021/jm900052j.

Lari Lehtiö ¹, 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

Affiliations

Affiliation

1 Structural Genomics Consortium, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-17177 Stockholm, Sweden.

PMID: 19354255 DOI: 10.1021/jm900052j

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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