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 A 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.
Kinoshita
Takayoshi
T
Exploratory Research Laboratories, Fujisawa Pharmaceutical Co. Ltd., 5-2-3, Tokodai, Tsukuba, 300-2698, Ibaraki, Japan. takayoshi_kinoshita@po.fujisawa.co.jp
Nakanishi
Isao
I
Warizaya
Masaichi
M
Iwashita
Akinori
A
Kido
Yoshiyuki
Y
Hattori
Kouji
K
Fujii
Takashi
T
D001665:Binding Sites; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008958:Models, Molecular; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism
D004791:Enzyme Inhibitors; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011994:Recombinant Proteins; D011065:Poly(ADP-ribose) Polymerases