A structural study using cryo‑electron microscopy detailed how CSN5i‑3 binds within the intact COP9 signalosome (CSN) complex, defining its orthosteric molecular‑glue mechanism. The work clarifies how CSN5i‑3 perturbs CSN enzymatic activity and protein–protein interactions, offering a mechanistic blueprint for designing hybrid inhibitors that act through induced proximity and active‑site engagement. The paper provides atomic‑level insight valuable to medicinal chemists and drug developers pursuing targeted protein regulation via molecular glues or degradation strategies. COP9 signalosome modulation is a technical strategy for altering ubiquitylation pathways; the study links structural binding modes to functional outcomes.