Hinge modifier approach opens door to drugging HECT E3 ligases

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Ubiquitylation is a vital post-translation modification that controls protein stability, activity and localization and is disrupted in many diseases. Around 650 E3 ubiquitin ligases each recognize a specific set of substrates and are potentially attractive therapeutic targets, but they often lack a confined active-site pocket amenable to small-molecule inhibition. Reporting in Cell, Rothman et al. discover allosteric inhibitors of the E3 ligase SMURF1 that restrict a hinge movement essential for catalysis. The inhibitors restore aberrant signalling pathways and pathology in animal models of pulmonary arterial hypertension (PAH).

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doi: https://doi.org/10.1038/d41573-025-00084-0

Rothman, A. M. K. et al. Therapeutic potential of allosteric HECT E3 ligase inhibition. Cell https://doi.org/10.1016/j.cell.2025.03.001 (2025)

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