5M5Q

COPS5(2-257) IN COMPLEX WITH A AZAINDOLE (COMPOUND 4)

Summary for 5M5Q

• Entry DOI: 10.2210/pdb5m5q/pdb
• Descriptor: COP9 signalosome complex subunit 5, ZINC ION, 1-[(3~{R})-3-(1~{H}-benzimidazol-2-yl)morpholin-4-yl]-3-[2-(4-methyl-2-phenyl-phenyl)-1~{H}-pyrrolo[2,3-b]pyridin-3-yl]propan-1-one, ... (5 entities in total)
• Functional Keywords: metal protease, cop9 signalosome, hydroxylase, hydrolase
• Biological source: Homo sapiens (Human)
• Cellular location: Cytoplasm: Q92905
• Total number of polymer chains: 1
• Total formula weight: 29676.20

Authors

Renatus, M.,Altmann, E. (deposition date: 2016-10-22, release date: 2017-01-11, Last modification date: 2024-05-01)

Primary citation

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, A.B.,Quancard, J.
Azaindoles as Zinc-Binding Small-Molecule Inhibitors of the JAMM Protease CSN5.
Angew. Chem. Int. Ed. Engl., 56:1294-1297, 2017

PubMed Abstract: CSN5 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.

PubMed: 27981705
DOI: 10.1002/anie.201608672

Experimental method

X-RAY DIFFRACTION (2.2 Å)