Database of articles cited by EMDB/PDB/SASBDB data

Keywords
Structure methods	All X-ray diffraction NMR electron microscopy small angle scattering neutron diffraction fiber diffraction powder diffraction infrared spectroscopy EPR fluorescence transfer theoretical model Hybrid
Author
Journal
IF	>30 >20 >10 >5 all

Title	CSN5i-3 is an orthosteric molecular glue inhibitor of COP9 signalosome.
Journal, issue, pages	Nature, Year 2026
Publish date	Feb 11, 2026
Authors	Huigang Shi / Xiaorong Wang / Clinton Yu / Haibin Mao / Fenglong Jiao / Merav Braitbard / Ben Shor / Zhongsheng Zhang / Thomas R Hinds / Shiyun Cao / Erkang Fan / Dina Schneidman-Duhovny / Lan Huang / Ning Zheng /
PubMed Abstract	Orthosteric inhibitors block enzyme active sites and prevent substrates from binding. Enhancing their specificity through substrate dependence seems inherently unlikely, as their mechanism hinges on ...Orthosteric inhibitors block enzyme active sites and prevent substrates from binding. Enhancing their specificity through substrate dependence seems inherently unlikely, as their mechanism hinges on direct competition rather than selective recognition. Here we show that a molecular glue mechanism unexpectedly imparts substrate-dependent potency to CSN5i-3, an orthosteric inhibitor of the COP9 signalosome (CSN). We first confirm that CSN5i-3 inhibits CSN, which catalyses NEDD8 (N8) deconjugation from the cullin-RING ubiquitin ligases, by occupying the active site of its catalytic subunit, CSN5, and directly competing with the iso-peptide bond substrate. Notably, the orthosteric inhibitor binds free CSN with only micromolar affinity, yet achieves nanomolar potency in blocking its deneddylase activity. Cryogenic electron microscopy structures of the enzyme-substrate-inhibitor complex reveal that active site-engaged CSN5i-3 occludes the substrate iso-peptide linkage while simultaneously extending an N8-binding exosite of CSN5, acting as a molecular glue to cement the N8-CSN5 interaction. The cooperativity of this trimolecular CSN5i-3-N8-CSN5 assembly, in turn, sequesters CSN5i-3 at its binding site, conferring high potency to the orthosteric inhibitor despite its low affinity for the free enzyme. Together, our findings highlight the modest affinity requirements of molecule glues for individual target proteins and establish orthosteric molecular glue inhibitors as a new class of substrate-dependent enzyme antagonists.
External links	Nature / PubMed:41673158
Methods	EM (single particle)
Resolution	2.96 - 4.6 Å
Structure data	47532 9e5z EMDB-47532, PDB-9e5z: Cryo-EM structure of COP9 signalosome Method: EM (single particle) / Resolution: 3.4 Å 47660 9e77 EMDB-47660, PDB-9e77: Cryo-EM structure of CSN-N8 in complex with CSN5i-3 Method: EM (single particle) / Resolution: 3.3 Å EMDB-47663: Cryo-EM structure of COP9 signalosome deneddylation state with cullin-5 Method: EM (single particle) / Resolution: 3.5 Å EMDB-47665: Focused map of COP9 signalosome deneddylation state with cullin-5 Method: EM (single particle) / Resolution: 3.7 Å 47698 9e81 EMDB-47698, PDB-9e81: Cryo-EM structure of COP9 signalosome in complex with CSN5i-3 Method: EM (single particle) / Resolution: 3.3 Å EMDB-47699: Focused map of COP9 signalosome deneddylation state with cullin-4A Method: EM (single particle) / Resolution: 3.5 Å EMDB-47701: Cryo-EM structure of COP9 signalosome deneddylation complex with cullin-2 Method: EM (single particle) / Resolution: 3.0 Å EMDB-47702: Focused map of COP9 signalosome deneddylation complex with cullin-2 Method: EM (single particle) / Resolution: 3.0 Å EMDB-47729: Cryo-EM structure of CSN-N8CUL1 complex with CSN5i-3 Method: EM (single particle) / Resolution: 3.0 Å EMDB-47767: Focused map of CSN-N8CUL1 in complex with CSN5i-3 Method: EM (single particle) / Resolution: 3.34 Å EMDB-47776: Cryo-EM structure of COP9 signalosome deneddylation complex with cullin-3 Method: EM (single particle) / Resolution: 3.93 Å 47976 9efm EMDB-47976, PDB-9efm: Cryo-EM structure of COP9 signalosome precatalytic state with neddylated cullin-1 Method: EM (single particle) / Resolution: 3.16 Å 47977 9efq EMDB-47977, PDB-9efq: Cryo-EM structure of COP9 signalosome precatalytic state with neddylated cullin-2 Method: EM (single particle) / Resolution: 2.96 Å 47981 9efv EMDB-47981, PDB-9efv: Cryo-EM structure of CSN-N8CUL1 in complex with CSN5i-3 Method: EM (single particle) / Resolution: 3.03 Å 47983 9eg1 EMDB-47983, PDB-9eg1: COP9 signalosome deneddylation complex with cullin-5 Method: EM (single particle) / Resolution: 3.52 Å EMDB-47985: Focused map of COP9 signalosome deneddylation complex with neddylated cullin-3 Method: EM (single particle) / Resolution: 4.6 Å 47986 9eg8 EMDB-47986, PDB-9eg8: Cryo-EM structure of COP9 signalosome precatalytic state with neddylated cullin-4A Method: EM (single particle) / Resolution: 3.39 Å 47990 9egl EMDB-47990, PDB-9egl: Cryo-EM structure of COP9 signalosome precatalytic state with neddylated cullin-3 Method: EM (single particle) / Resolution: 3.93 Å 71639 9ph4 EMDB-71639, PDB-9ph4: Cryo-EM structure of COP9 signalosome in complex with CSN5i-1a Method: EM (single particle) / Resolution: 3.0 Å
Chemicals	ChemComp-ZN: Unknown entry ChemComp-6LT: 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 PDB-1ch3: RECOMBINANT SPERM WHALE MYOGLOBIN L89W MUTANT (MET)
Source	homo sapiens (human)
Keywords	METAL BINDING PROTEIN / COP9 / COP9 signalosome / signalosome / deneddylation / CSN5 / metalloprotease / SIGNALING PROTEIN / NEDD8 / CSN5i-3 / N8CUL1 / CSN / cullin-2 / CSN-N8CUL2 / CUL2 / othosteric molecular glue / N8CUL5 / CUL5 / N8CUL4A / CUL4A / deneddylation complex / CSN5i-1a