6XON

DCN1 bound to inhibitor 9

6XON の概要

• エントリーDOI: 10.2210/pdb6xon/pdb
• 分子名称: Lysozyme DCN1-like protein 1 chimera, (2S)-N-[(2S)-2-cyclohexyl-2-({N-propanoyl-3-[6-(propan-2-yl)-1,3-benzothiazol-2-yl]-L-alanyl}amino)ethyl]-4-(dimethylamino)-2-methylbutanamide (3 entities in total)
• 機能のキーワード: inhibitor, ligase, ligase-ligase inhibitor complex, ligase/ligase inhibitor
• 由来する生物種: Enterobacteria phage T4; 詳細
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 44919.25

構造登録者

Stuckey, J.A. (登録日: 2020-07-07, 公開日: 2021-06-02, 最終更新日: 2024-10-16)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.8 Å)