6XOQ

DCN1 covalently bound to inhibitor 4

Summary for 6XOQ

• Entry DOI: 10.2210/pdb6xoq/pdb
• Related: 6XOL 6XOM 6XON 6XOO 6XOP
• Descriptor: Lysozyme, DCN1-like protein 1 chimera, (2E)-N-[(2S)-2-cyclohexyl-2-({N-propanoyl-3-[6-(propan-2-yl)-1,3-benzothiazol-2-yl]-L-alanyl}amino)ethyl]-4-(morpholin-4-yl)but-2-enamide (3 entities in total)
• Functional Keywords: inhibitor, ligase, ligase-ligase inhibitor complex, ligase/ligase inhibitor
• Biological source: Enterobacteria phage T4; More
• Total number of polymer chains: 1
• Total formula weight: 44945.25

Authors

Stuckey, J.A. (deposition date: 2020-07-07, release date: 2021-06-02, Last modification date: 2023-10-18)

Primary citation

Zhou, H.,Lu, J.,Chinnaswamy, K.,Stuckey, J.A.,Liu, L.,McEachern, D.,Yang, C.Y.,Bernard, D.,Shen, H.,Rui, L.,Sun, Y.,Wang, S.
Selective inhibition of cullin 3 neddylation through covalent targeting DCN1 protects mice from acetaminophen-induced liver toxicity.
Nat Commun, 12:2621-2621, 2021

PubMed Abstract: Cullin-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.

PubMed: 33976147
DOI: 10.1038/s41467-021-22924-4

Experimental method

X-RAY DIFFRACTION (2.07 Å)