一种强效的 DCN1-UBC12 相互作用小分子抑制剂，可选择性阻断泛素样蛋白连接酶 E3 复合物 CUL3 的 neddylation。
A potent small-molecule inhibitor of the DCN1-UBC12 interaction that selectively blocks cullin 3 neddylation.
机构信息
Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, 48109, USA.
Department of Pathology, University of Michigan, Ann Arbor, Michigan, 48109, USA.
出版信息
Nat Commun. 2017 Oct 27;8(1):1150. doi: 10.1038/s41467-017-01243-7.
The Cullin-RING E3 ubiquitin ligases (CRLs) regulate homeostasis of ~20% of cellular proteins and their activation require neddylation of their cullin subunit. Cullin neddylation is modulated by a scaffolding DCN protein through interactions with both the cullin protein and an E2 enzyme such as UBC12. Here we report the development of DI-591 as a high-affinity, cell-permeable small-molecule inhibitor of the DCN1-UBC12 interaction. DI-591 binds to purified recombinant human DCN1 and DCN2 proteins with K values of 10-12 nM, and disrupts the DCN1-UBC12 interaction in cells. Treatment with DI-591 selectively converts cellular cullin 3 into an un-neddylated inactive form with no or minimum effect on other cullin members. Our data firmly establish a previously unrecognized specific role of the DCN1-UBC12 interaction for cellular neddylation of cullin 3. DI-591 is an excellent probe compound to investigate the role of the cullin 3 CRL ligase in biological processes and human diseases.
Cullin-RING E3 泛素连接酶（CRLs）调节约 20%的细胞蛋白的内稳态，其激活需要其 Cullin 亚基的 neddylation。Cullin 的 neddylation 由支架 DCN 蛋白通过与 Cullin 蛋白和 E2 酶（如 UBC12）的相互作用来调节。在这里，我们报告了 DI-591 的开发，它是一种高亲和力、细胞渗透性的小分子抑制剂，可抑制 DCN1-UBC12 相互作用。DI-591 以 10-12 nM 的 Kd 值与纯化的重组人 DCN1 和 DCN2 蛋白结合，并在细胞中破坏 DCN1-UBC12 相互作用。用 DI-591 处理可选择性地将细胞内 Cullin 3 转化为未 neddylated 的无活性形式，对其他 Cullin 成员几乎没有或没有影响。我们的数据明确确立了 DCN1-UBC12 相互作用在细胞内 Cullin 3 neddylation 中的以前未被认识到的特定作用。DI-591 是研究 Cullin 3 CRL 连接酶在生物学过程和人类疾病中的作用的极好的探针化合物。
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