5JOG

CRYSTAL STRUCTURE OF CSN5(2-257) IN COMPLEX WITH CNS5i-3

5JOG の概要

• エントリーDOI: 10.2210/pdb5jog/pdb
• 分子名称: COP9 signalosome complex subunit 5, ZINC ION, 3-(difluoromethyl)-N-{6-[(5S,6S)-6-hydroxy-6,7,8,9-tetrahydro-5H-imidazo[1,5-a]azepin-5-yl][1,1'-biphenyl]-3-yl}-1-(propan-2-yl)-1H-pyrazole-5-carboxamide, ... (4 entities in total)
• 機能のキーワード: cop9 signalosome, metal protease, inhibitor, hydroxylase
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Cytoplasm: Q92905
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 29521.95

構造登録者

Renatus, M.,Wiesmann, C. (登録日: 2016-05-02, 公開日: 2016-11-02, 最終更新日: 2024-01-10)

主引用文献

Schlierf, A.,Altmann, E.,Quancard, J.,Jefferson, A.B.,Assenberg, R.,Renatus, M.,Jones, M.,Hassiepen, U.,Schaefer, M.,Kiffe, M.,Weiss, A.,Wiesmann, C.,Sedrani, R.,Eder, J.,Martoglio, B.
Targeted inhibition of the COP9 signalosome for treatment of cancer.
Nat Commun, 7:13166-13166, 2016

PubMed Abstract: The COP9 signalosome (CSN) is a central component of the activation and remodelling cycle of cullin-RING E3 ubiquitin ligases (CRLs), the largest enzyme family of the ubiquitin-proteasome system in humans. CRLs are implicated in the regulation of numerous cellular processes, including cell cycle progression and apoptosis, and aberrant CRL activity is frequently associated with cancer. Remodelling of CRLs is initiated by CSN-catalysed cleavage of the ubiquitin-like activator NEDD8 from CRLs. Here we describe CSN5i-3, a potent, selective and orally available inhibitor of CSN5, the proteolytic subunit of CSN. The compound traps CRLs in the neddylated state, which leads to inactivation of a subset of CRLs by inducing degradation of their substrate recognition module. CSN5i-3 differentially affects the viability of tumour cell lines and suppresses growth of a human xenograft in mice. Our results provide insights into how CSN regulates CRLs and suggest that CSN5 inhibition has potential for anti-tumour therapy.

PubMed: 27774986
DOI: 10.1038/ncomms13166

実験手法

X-RAY DIFFRACTION (2.46 Å)