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

共 19 条

[11] BRCA2-deficient CAPAN-1 cells are extremely sensitive to the inhibition of poly (ADP-Ribose) polymerase [J].

McCabe, N ;

Lord, CJ ;

Tutt, ANJ ;

Martin, NMB ;

Smith, GCM ;

Ashworth, A .

CANCER BIOLOGY & THERAPY, 2005, 4 (09) :934-936

[12] A newly synthesized poly(ADP-ribose) polymerase inhibitor, DR2313 [2-methyl-3,5,7,8-tetrahydrothiopyrano[4,3-d]pyrimidine-4-one]:: Pharmacological profiles, neuroprotective effects, and therapeutic time window in cerebral ischemia in rats [J].

Nakajima, H ;

Kakui, N ;

Ohkuma, K ;

Ishikawa, M ;

Hasegawa, T .

JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 2005, 312 (02) :472-481

[13] The use of differential scanning fluorimetry to detect ligand interactions that promote protein stability [J].

Niesen, Frank H. ;

Berglund, Helena ;

Vedadi, Masoud .

NATURE PROTOCOLS, 2007, 2 (09) :2212-2221

[14] Crystal structure of the catalytic fragment of murine poly(ADP-ribose) polymerase-2 [J].

Oliver, AW ;

Amé, JC ;

Roe, SM ;

Good, V ;

de Murcia, G ;

Pearl, LH .

NUCLEIC ACIDS RESEARCH, 2004, 32 (02) :456-464

[15] Role of Poly(ADP-ribose) polymerase 1 (PARP-1) in cardiovascular diseases:: The therapeutic potential of PARP inhibitors [J].

Pacher, Pal ;

Szabo, Csaba .

CARDIOVASCULAR DRUG REVIEWS, 2007, 25 (03) :235-260

[16] New inhibitors of poly(ADP-ribose) polymerase (PARP) [J].

Peukert, S ;

Schwahn, U .

EXPERT OPINION ON THERAPEUTIC PATENTS, 2004, 14 (11) :1531-1551

[17] Structure of the catalytic fragment of poly(ADP-ribose) polymerase from chicken [J].

Ruf, A ;

DeMurcia, JM ;

DeMurcia, GM ;

Schulz, GE .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1996, 93 (15) :7481-7485

[18] ROLE OF POLY(ADP-RIBOSE) FORMATION IN DNA-REPAIR [J].

SATOH, MS ;

LINDAHL, T .

NATURE, 1992, 356 (6367) :356-358

[19] Poly(ADP-ribose):: novel functions for an old molecule [J].

Schreiber, Valerie ;

Dantzer, Francoise ;

Ame, Jean-Christophe ;

de Murcia, Gilbert .

NATURE REVIEWS MOLECULAR CELL BIOLOGY, 2006, 7 (07) :517-528

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