Suramin inhibits cullin-RING E3 ubiquitin ligases.
Suramin inhibits cullin-RING E3 ubiquitin ligases.
复制标题
Suramin 抑制 cullin-RING E3 泛素连接酶。
DOI：
10.1073/pnas.1601089113
复制
发表时间：
2016
影响因子：
11.1
通讯作者：
Pan Zhen-Qiang
中科院分区：
文献类型：
--
作者：
Wu Kenneth;Chong Robert A;Yu Qing;Bai Jin;Spratt Donald E;Ching Kevin;Lee Chan;Miao Haibin;Tappin Inger;Hurwitz Jerard;Zheng Ning;Shaw Gary S;Sun Yi;Felsenfeld Dan P;Sanchez Roberto;Zheng Jun-Nian;Pan Zhen-Qiang
Cullin-RING E3泛素连接酶（CRL）通过指导蛋白酶体降解大量蛋白质底物来控制无数生物过程。CRL活性的关键是通过E3的cullin保守的碱性峡谷和E2酶的酸性C末端之间的静电相互作用募集E2泛素缀合酶Cdc 34。该报告表明，小分子化合物苏拉明，可以通过破坏其招募Cdc 34的能力来抑制CRL活性。苏拉明，一种抗锥虫药物，也具有抗肿瘤活性，通过基于荧光的高通量筛选确定在这里作为泛素化的抑制剂。苏拉明显示靶向cullin 1的保守基本峡谷，并阻止其与Cdc 34的结合。苏拉明抑制多种含有cullin 2、3和4A的CRL复合物的活性。当引入细胞，苏拉明诱导CRL底物的积累。这些观察有助于开发一种通过小分子调节剂靶向E2-E3界面来调节泛素化的策略。
Cullin-RING E3 ubiquitin ligases (CRL) control a myriad of biological processes by directing numerous protein substrates for proteasomal degradation. Key to CRL activity is the recruitment of the E2 ubiquitin-conjugating enzyme Cdc34 through electrostatic interactions between E3′s cullin conserved basic canyon and the acidic C terminus of the E2 enzyme. This report demonstrates that a small-molecule compound, suramin, can inhibit CRL activity by disrupting its ability to recruit Cdc34. Suramin, an antitrypansomal drug that also possesses antitumor activity, was identified here through a fluorescence-based high-throughput screen as an inhibitor of ubiquitination. Suramin was shown to target cullin 1’s conserved basic canyon and to block its binding to Cdc34. Suramin inhibits the activity of a variety of CRL complexes containing cullin 2, 3, and 4A. When introduced into cells, suramin induced accumulation of CRL substrates. These observations help develop a strategy of regulating ubiquitination by targeting an E2–E3 interface through small-molecule modulators.