Inhibitor‐induced structural change of the active site of human poly(ADP‐ribose) polymerase

The crystal structure of human recombinant poly(ADP‐ribose) polymerase (PARP) complexed with a potent inhibitor, FR257517, was solved at 3.0 Å resolution. The fluorophenyl part of the inhibitor induces an amazing conformational change in the active site of PARP by motion of the side chain of the amino acid, Arg878, which forms the bottom of the active site. Consequently, a corn‐shaped hydrophobic subsite, which consists of the side chains of Leu769, Ile879, Pro881, and the methylene chain of Arg878, newly emerges from the well‐known active site.

[1]  J. Griesenbeck,et al.  The role of poly(ADP-ribosyl)ation. , 1997, Reviews of physiology, biochemistry and pharmacology.

[2]  J. M. Murcia,et al.  Poly(ADP-ribose) polymerase: a molecular nick-sensor. , 1994, Trends in biochemical sciences.

[3]  Large-format imaging plate and weissenberg camera for accurate protein crystallographic data collection using synchrotron radiation. , 1997, Journal of synchrotron radiation.

[4]  Z. Otwinowski,et al.  [20] Processing of X-ray diffraction data collected in oscillation mode. , 1997, Methods in enzymology.

[5]  G. Poirier,et al.  Poly(ADP-ribosyl)ation reactions in the regulation of nuclear functions. , 1999, The Biochemical journal.

[6]  N. Curtin,et al.  Synthesis and Biological Properties of Benzimidazole Inhibitors of the DNA Repair Enzyme Poly ( ADP-ribose ) Polymerase , 2022 .

[7]  V. Schreiber,et al.  Involvement of poly(ADP-ribose) polymerase in base excision repair. , 1999, Biochimie.

[8]  N. Curtin,et al.  Novel tricyclic poly(ADP-ribose) polymerase-1 inhibitors with potent anticancer chemopotentiating activity: design, synthesis, and X-ray cocrystal structure. , 2002, Journal of medicinal chemistry.

[9]  N. Curtin,et al.  Potentiation of temozolomide and topotecan growth inhibition and cytotoxicity by novel poly(adenosine diphosphoribose) polymerase inhibitors in a panel of human tumor cell lines. , 2000, Clinical cancer research : an official journal of the American Association for Cancer Research.

[10]  G. Schulz,et al.  The mechanism of the elongation and branching reaction of poly(ADP-ribose) polymerase as derived from crystal structures and mutagenesis. , 1998, Journal of molecular biology.