6xoq
DCN1 covalently bound to inhibitor 4DCN1 covalently bound to inhibitor 4
Structural highlights
FunctionD9IEF7_BPT4 DCNL1_HUMAN Part of an E3 ubiquitin ligase complex for neddylation. Required for neddylation of cullin components of E3 cullin-RING ubiquitin ligase complexes by enhancing the rate of cullins neddylation. Functions to recruit the NEDD8-charged E2 enzyme to the cullin component. Involved in the release of inhibitory effets of CAND1 on cullin-RING ligase E3 complex assembly and activity. Acts also as an oncogene facilitating malignant transformation and carcinogenic progression (By similarity). Publication Abstract from PubMedCullin-RING E3 ligases (CRLs) regulate the turnover of approximately 20% of mammalian cellular proteins. Neddylation of individual cullin proteins is essential for the activation of each CRL. We report herein the discovery of DI-1548 and DI-1859 as two potent, selective and covalent DCN1 inhibitors. These inhibitors selectively inhibit neddylation of cullin 3 in cells at low nanomolar concentrations and are 2-3 orders of magnitude more potent than our previously reported reversible DCN1 inhibitor. Mass spectrometric analysis and co-crystal structures reveal that these compounds employ a unique mechanism of covalent bond formation with DCN1. DI-1859 induces a robust increase of NRF2 protein, a CRL3 substrate, in mouse liver and effectively protects mice from acetaminophen-induced liver damage. Taken together, this study demonstrates the therapeutic potential of selective inhibition of cullin neddylation. Selective inhibition of cullin 3 neddylation through covalent targeting DCN1 protects mice from acetaminophen-induced liver toxicity.,Zhou H, Lu J, Chinnaswamy K, Stuckey JA, Liu L, McEachern D, Yang CY, Bernard D, Shen H, Rui L, Sun Y, Wang S Nat Commun. 2021 May 11;12(1):2621. doi: 10.1038/s41467-021-22924-4. PMID:33976147[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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