An Allosteric Inhibitor of the Human Cdc34 Ubiquitin-Conjugating Enzyme
An Allosteric Inhibitor of the Human Cdc34 Ubiquitin-Conjugating Enzyme
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DOI：
10.1016/j.cell.2011.05.039
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发表时间：
2011-06-24
期刊：
影响因子：
64.5
通讯作者：
Sicheri, Frank
中科院分区：
文献类型：
--
作者：
Ceccarelli, Derek F.;Tang, Xiaojing;Sicheri, Frank
在泛素-蛋白酶体系统(UPS)中，E2酶介导泛素与底物的结合，从而控制蛋白质的稳定性和相互作用。E2酶hCdc34与E3酶的cullin-ring(CRL)超家族一起催化数百种蛋白质的泛素化。我们发现了一种名为CC0651的小分子，它可以选择性地抑制hCDC34。结构测定表明，CC0651插入hCDC34上远离催化部位的隐蔽结合口袋，导致E2二级结构元件微妙但大规模置换。CC0651类似物抑制人癌细胞株的增殖，并引起SCFSkp2底物p27(Kip1)的积聚。CC0651不影响hCDC34与E1或E3酶的相互作用或泛素硫酸酯的形成，而是干扰泛素向受体赖氨酸残基的排放。因此，E2酶对非催化部位的抑制很敏感，可能代表了UPS中一类可行的药物靶点。
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.