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

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 Sun; Shaomeng Wang

doi:10.1038/s41467-017-01243-7

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

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 Sun
, Shaomeng Wang

Research output: Contribution to journal › Article › peer-review

91 Scopus citations

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.

Original language	English
Article number	1150
Journal	Nature Communications
Volume	8
Issue number	1
DOIs	https://doi.org/10.1038/s41467-017-01243-7
State	Published - 1 Dec 2017

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

abstract = "The Cullin-RING E3 ubiquitin ligases (CRLs) regulate homeostasis of \textasciitilde{}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.",

author = "Haibin Zhou and Jianfeng Lu and Liu Liu and Denzil Bernard and Yang, \{Chao Yie\} and Ester Fernandez-Salas and Krishnapriya Chinnaswamy and Stephanie Layton and Jeanne Stuckey and Qing Yu and Weihua Zhou and Zhenqiang Pan and Yi Sun and Shaomeng Wang",

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doi = "10.1038/s41467-017-01243-7",

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T1 - A potent small-molecule inhibitor of the DCN1-UBC12 interaction that selectively blocks cullin 3 neddylation

AU - Zhou, Haibin

AU - Lu, Jianfeng

AU - Liu, Liu

AU - Bernard, Denzil

AU - Yang, Chao Yie

AU - Fernandez-Salas, Ester

AU - Chinnaswamy, Krishnapriya

AU - Layton, Stephanie

AU - Stuckey, Jeanne

AU - Yu, Qing

AU - Zhou, Weihua

AU - Pan, Zhenqiang

AU - Sun, Yi

AU - Wang, Shaomeng

PY - 2017/12/1

Y1 - 2017/12/1

N2 - 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.

AB - 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.

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DO - 10.1038/s41467-017-01243-7

M3 - Article

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AN - SCOPUS:85032467334

SN - 2041-1723

VL - 8

JO - Nature Communications

JF - Nature Communications

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M1 - 1150

ER -

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

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