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Abstract
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 Ki 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.
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Details
1 Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
2 Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA
3 Life Sciences Institute, University of Michigan, Ann Arbor, Michigan, USA
4 Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China
5 Division of Radiation and Cancer Biology, Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan, USA
6 Department of Oncological Sciences, Mount Sinai School of Medicine, New York, New York, USA
7 Division of Radiation and Cancer Biology, Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan, USA; Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China
8 Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA; Department of Pharmacology, University of Michigan, Ann Arbor, Michigan, USA; Department of Medicinal Chemistry, University of Michigan, Ann Arbor, Michigan, USA