An Allosteric Inhibitor of the Human Cdc34 Ubiquitin-Conjugating Enzyme

被引：196

作者：

Ceccarelli, Derek F. ^{[2
]}

Tang, Xiaojing ^{[2
]}

Pelletier, Benoit ^{[8
]}

Orlicky, Stephen ^{[2
]}

Xie, Weilin ^{[1
]}

Plantevin, Veronique ^{[1
]}

Neculai, Dante ^{[2
,5
]}

Chou, Yang-Chieh ^{[2
]}

Ogunjimi, Abiodun ^{[2
]}

Al-Hakim, Abdallah ^{[2
]}

Varelas, Xaralabos ^{[2
]}

Koszela, Joanna ^{[6
]}

Wasney, Gregory A. ^{[5
]}

Vedadi, Masoud ^{[5
]}

Dhe-Paganon, Sirano ^{[5
]}

Cox, Sarah ^{[1
]}

Xu, Shuichan ^{[1
]}

Lopez-Girona, Antonia ^{[1
]}

Mercurio, Frank ^{[1
]}

Wrana, Jeff ^{[2
]}

Durocher, Daniel ^{[2
]}

Meloche, Sylvain ^{[3
,4
,8
]}

Webb, David R. ^{[1
]}

Tyers, Mike ^{[2
,6
,7
]}

Sicheri, Frank ^{[2
,7
]}

机构：

[1] Celgene Signal Res Div, San Diego, CA 92121 USA

[2] Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Ctr Syst Biol, Toronto, ON M5G 1X5, Canada

[3] Univ Montreal, Program Mol Biol, Montreal, PQ H3C 3J7, Canada

[4] Univ Montreal, Dept Pharmacol, Montreal, PQ H3C 3J7, Canada

[5] Struct Genom Consortium, Toronto, ON M5G 1L7, Canada

[6] Univ Edinburgh, Wellcome Trust Ctr Cell Biol, Edinburgh EH9 3JR, Midlothian, Scotland

[7] Univ Toronto, Dept Mol Genet, Toronto, ON M5S 1A8, Canada

[8] Univ Montreal, Inst Rech Immunol & Cancerol, Montreal, PQ H3C 3J7, Canada

来源：

CELL | 2011年 / 145卷 / 07期

基金：

加拿大健康研究院; 美国国家卫生研究院;

关键词：

F-BOX PROTEINS; CELL-DIVISION; LIGASE; ACTIVATION; SUBSTRATE; E2; PROTEOLYSIS; P27(KIP1); COMPLEX; E3;

D O I：

10.1016/j.cell.2011.05.039

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

In the ubiquitin-proteasome system (UPS), E2 enzymes mediate the conjugation of ubiquitin to substrates and thereby control protein stability and interactions. The E2 enzyme hCdc34 catalyzes the ubiquitination of hundreds of proteins in conjunction with the cullin-RING (CRL) superfamily of E3 enzymes. We identified a small molecule termed CC0651 that selectively inhibits hCdc34. Structure determination revealed that CC0651 inserts into a cryptic binding pocket on hCdc34 distant from the catalytic site, causing subtle but wholesale displacement of E2 secondary structural elements. CC0651 analogs inhibited proliferation of human cancer cell lines and caused accumulation of the SCFSkp2 substrate p27(Kip1). CC0651 does not affect hCdc34 interactions with E1 or E3 enzymes or the formation of the ubiquitin thioester but instead interferes with the discharge of ubiquitin to acceptor lysine residues. E2 enzymes are thus susceptible to noncatalytic site inhibition and may represent a viable class of drug target in the UPS.

引用

页码：1075 / 1087

页数：13

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