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A potent small-molecule inhibitor of the DCN1-UBC12 interaction that selectively blocks cullin 3 neddylation

Author

Listed:
  • Haibin Zhou

    (University of Michigan)

  • Jianfeng Lu

    (University of Michigan)

  • Liu Liu

    (University of Michigan)

  • Denzil Bernard

    (University of Michigan)

  • Chao-Yie Yang

    (University of Michigan)

  • Ester Fernandez-Salas

    (University of Michigan)

  • Krishnapriya Chinnaswamy

    (University of Michigan)

  • Stephanie Layton

    (University of Michigan)

  • Jeanne Stuckey

    (University of Michigan)

  • Qing Yu

    (Zhejiang University School of Medicine)

  • Weihua Zhou

    (University of Michigan)

  • Zhenqiang Pan

    (Mount Sinai School of Medicine)

  • Yi Sun

    (University of Michigan
    Zhejiang University School of Medicine)

  • Shaomeng Wang

    (University of Michigan
    University of Michigan
    University of Michigan)

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 K i 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.

Suggested Citation

  • Haibin Zhou & Jianfeng Lu & Liu Liu & Denzil Bernard & Chao-Yie Yang & Ester Fernandez-Salas & Krishnapriya Chinnaswamy & Stephanie Layton & Jeanne Stuckey & Qing Yu & Weihua Zhou & Zhenqiang Pan & Yi, 2017. "A potent small-molecule inhibitor of the DCN1-UBC12 interaction that selectively blocks cullin 3 neddylation," Nature Communications, Nature, vol. 8(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-01243-7
    DOI: 10.1038/s41467-017-01243-7
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