5JOG

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

Summary for 5JOG

• Entry DOI: 10.2210/pdb5jog/pdb
• Descriptor: 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)
• Functional Keywords: cop9 signalosome, metal protease, inhibitor, hydroxylase
• Biological source: Homo sapiens (Human)
• Cellular location: Cytoplasm: Q92905
• Total number of polymer chains: 1
• Total formula weight: 29521.95

Authors

Renatus, M.,Wiesmann, C. (deposition date: 2016-05-02, release date: 2016-11-02, Last modification date: 2024-01-10)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.46 Å)