Structural Basis for Inhibitor Specificity in Human Poly(ADP-ribose) Polymerase-3

被引：94

作者：

Lehtio, Lari ^{[2
]}

Jemth, Ann-Sofie ^{[1
]}

Collins, Ruairi ^{[2
]}

Loseva, Olga ^{[1
]}

Johansson, Andreas ^{[2
]}

Markova, Natalia ^{[2
,3
]}

Hammarstrom, Martin ^{[2
]}

Flores, Alex ^{[2
]}

Holmberg-Schiavone, Lovisa ^{[2
]}

Weigelt, Johan ^{[2
]}

Helleday, Thomas ^{[1
,4
]}

Schuler, Herwig ^{[2
]}

Karlberg, Tobias ^{[2
]}

机构：

[1] Stockholm Univ, Dept Genet Microbiol & Toxicol, SE-10691 Stockholm, Sweden

[2] Karolinska Inst, Dept Med Biochem & Biophys, Struct Genom Consortium, SE-17177 Stockholm, Sweden

[3] iNovacia AB, SE-11251 Stockholm, Sweden

[4] Univ Oxford, Gray Inst Radiat Oncol & Biol, Oxford OX3 7DQ, England

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2009年 / 52卷 / 09期

基金：

英国惠康基金; 瑞典研究理事会; 英国医学研究理事会;

关键词：

DNA-REPAIR; CATALYTIC FRAGMENT; CEREBRAL-ISCHEMIA; STABILITY; PARP-1; CELLS;

D O I：

10.1021/jm900052j

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页码：3108 / 3111

页数：4

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