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Drs. Ning Zheng and Huigang Shi Publish in NATURE

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Prof. Ning Zheng and Prof. Lan Huang (UCI), co-corresponding authors of the study, together with Dr. Huigang Shi, published in Nature titled  “CSN5i-3 is an orthosteric molecular glue inhibitor of COP9 signalosome.”  The team elucidated the structure and regulatory mechanism of the COP9 signalosome, a conserved multi-protein complex that controls the activity of the largest family of ubiquitin ligases in human cells and plays a central role in protein homeostasis. The team discovered a small molecule, CSN5i-3, that directly occupies the enzyme’s catalytic site while simultaneously stabilizing the enzyme–substrate complex. These findings establish a new class of inhibitors termed Orthosteric Molecular Glue (OMG) inhibitors. Unlike canonical orthosteric inhibitors, OMG inhibitors confer substrate-dependent inhibition, enabling highly precise modulation of specific substrate–enzyme pairs rather than indiscriminately blocking the enzyme itself. This conceptual advance provides a potential strategy to mitigate on-target toxicity that has limited many clinical-stage inhibitors.