5m5q | pdb_00005m5q
COPS5(2-257) IN COMPLEX WITH A AZAINDOLE (COMPOUND 4)
Structural highlights
Function[CSN5_HUMAN] Probable protease subunit of the COP9 signalosome complex (CSN), a complex involved in various cellular and developmental processes. The CSN complex is an essential regulator of the ubiquitin (Ubl) conjugation pathway by mediating the deneddylation of the cullin subunits of the SCF-type E3 ligase complexes, leading to decrease the Ubl ligase activity of SCF-type complexes such as SCF, CSA or DDB2. The complex is also involved in phosphorylation of p53/TP53, c-jun/JUN, IkappaBalpha/NFKBIA, ITPK1 and IRF8, possibly via its association with CK2 and PKD kinases. CSN-dependent phosphorylation of TP53 and JUN promotes and protects degradation by the Ubl system, respectively. In the complex, it probably acts as the catalytic center that mediates the cleavage of Nedd8 from cullins. It however has no metalloprotease activity by itself and requires the other subunits of the CSN complex. Interacts directly with a large number of proteins that are regulated by the CSN complex, confirming a key role in the complex. Promotes the proteasomal degradation of BRSK2.[1] [2] [3] [4] [5] [6] [7] Publication Abstract from PubMedCSN5 is the zinc metalloprotease subunit of the COP9 signalosome (CSN), which is an important regulator of cullin-RING E3 ubiquitin ligases (CRLs). CSN5 is responsible for the cleavage of NEDD8 from CRLs, and blocking deconjugation of NEDD8 traps the CRLs in a hyperactive state, thereby leading to auto-ubiquitination and ultimately degradation of the substrate recognition subunits. Herein, we describe the discovery of azaindoles as a new class of CSN5 inhibitors, which interact with the active-site zinc ion of CSN5 through an unprecedented binding mode. The best compounds inhibited CSN5 with nanomolar potency, led to degradation of the substrate recognition subunit Skp2 in cells, and reduced the viability of HCT116 cells. Azaindoles as Zinc-Binding Small-Molecule Inhibitors of the JAMM Protease CSN5.,Altmann E, Erbel P, Renatus M, Schaefer M, Schlierf A, Druet A, Kieffer L, Sorge M, Pfister K, Hassiepen U, Jones M, Ruedisser S, Ostermeier D, Martoglio B, Jefferson AB, Quancard J Angew Chem Int Ed Engl. 2017 Jan 24;56(5):1294-1297. doi: 10.1002/anie.201608672., Epub 2016 Dec 16. PMID:27981705[8] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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