5UFI

DCN1 bound to DI-591

Summary for 5UFI

• Entry DOI: 10.2210/pdb5ufi/pdb
• Related PRD ID: PRD_002263
• Descriptor: DCN1-like protein 1, N-[(1S)-1-cyclohexyl-2-{[3-(morpholin-4-yl)propanoyl]amino}ethyl]-N~2~-propanoyl-3-[6-(propan-2-yl)-1,3-benzothiazol-2-yl]-L-alaninamide (3 entities in total)
• Functional Keywords: e3 ligase, complex, ligase-inhibitor complex, ligase/inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Nucleus : Q96GG9
• Total number of polymer chains: 4
• Total formula weight: 107350.66

Authors

Stuckey, J. (deposition date: 2017-01-04, release date: 2017-11-01, Last modification date: 2024-04-03)

Primary citation

Zhou, H.,Lu, J.,Liu, L.,Bernard, D.,Yang, C.Y.,Fernandez-Salas, E.,Chinnaswamy, K.,Layton, S.,Stuckey, J.,Yu, Q.,Zhou, W.,Pan, Z.,Sun, Y.,Wang, S.
A potent small-molecule inhibitor of the DCN1-UBC12 interaction that selectively blocks cullin 3 neddylation.
Nat Commun, 8:1150-1150, 2017

PubMed 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 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.

PubMed: 29074978
DOI: 10.1038/s41467-017-01243-7

Experimental method

X-RAY DIFFRACTION (2.58 Å)