2. Academic Validation
  3. Selective ubiquitination of drug-like small molecules by the ubiquitin ligase HUWE1

Selective ubiquitination of drug-like small molecules by the ubiquitin ligase HUWE1

  • Nat Commun. 2025 Sep 2;16(1):8182. doi: 10.1038/s41467-025-63442-x.
Barbara Orth # 1,  Pavel Pohl # 1,  Florian Aust 1,  Yanlong Ji 2 3,  Ayshwarya Seenivasan 1,  Olexandr Dybkov 2,  Xiaojun Julia Liang 4 5 6,  Lars Bock 7,  Florian Leidner 7,  Sophie Levantovsky 8,  Patrick Schardey 1,  Pascal Sander 5,  Nathanael J Disch 5,  Masanja L Trautz 5,  Athanasia Mizi 9,  Argyris Papantonis 9,  Christof Lenz 3,  Helmut Grubmüller 7,  Wieland Steinchen 10 11,  Christian Behrends 8,  Henning Urlaub 2 3,  Matthias Gehringer 4 5 6,  Sonja Lorenz 12
Affiliations

Affiliations

  • 1 Max Planck Institute for Multidisciplinary Sciences, Research Group 'Ubiquitin Signaling Specificity', Göttingen, Germany.
  • 2 Max Planck Institute for Multidisciplinary Sciences, Research Group 'Bioanalytical Mass Spectrometry', Göttingen, Germany.
  • 3 Bioanalytics, Department of Clinical Chemistry, University Medical Center Göttingen, Göttingen, Germany.
  • 4 Department for Medicinal Chemistry, Institute for Biomedical Engineering, Faculty of Medicine, Eberhard Karls University Tübingen, Tübingen, Germany.
  • 5 Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmaceutical Sciences, Eberhard Karls University Tübingen, Tübingen, Germany.
  • 6 Cluster of Excellence iFIT (EXC 2180) 'Image-Guided & Functionally Instructed Tumor Therapies', Eberhard Karls University Tübingen, Tübingen, Germany.
  • 7 Max Planck Institute for Multidisciplinary Sciences, Department of Theoretical and Computational Biophysics, Göttingen, Germany.
  • 8 Munich Cluster for Systems Neurology (SyNergy), Faculty of Medicine, Ludwig-Maximilians-University München, Munich, Germany.
  • 9 Institute of Pathology, University Medical Center Göttingen, Göttingen, Germany.
  • 10 Department of Chemistry, Philipps University Marburg, Marburg, Germany.
  • 11 Center for Synthetic Microbiology, Philipps University Marburg, Marburg, Germany.
  • 12 Max Planck Institute for Multidisciplinary Sciences, Research Group 'Ubiquitin Signaling Specificity', Göttingen, Germany. sonja.lorenz@mpinat.mpg.de.
  • # Contributed equally.
PMID: 40897715 DOI: 10.1038/s41467-025-63442-x
Abstract

The ubiquitin system regulates eukaryotic physiology by modifying myriad substrate proteins. Substrate specificity and the assembly of ubiquitin signals are determined by ubiquitin ligases, some of which also modify non-protein biomolecules. Here we expand this substrate realm, revealing that the human Ligase HUWE1 can target drug-like small molecules. We demonstrate that compounds previously reported as HUWE1 inhibitors present substrates of their target Ligase. Compound ubiquitination is driven by the canonical catalytic cascade, linking ubiquitin to the compound's primary amino group. In vitro, the modification is selectively catalyzed by HUWE1, allowing the compounds to compete with protein substrates. We establish cellular detection methods, confirming HUWE1 promotes - but does not exclusively drive - compound ubiquitination in cells. Converting the existing compounds into specific HUWE1 substrates or inhibitors thus requires enhanced specificity. More broadly, our findings open avenues for harnessing the ubiquitin system to transform exogenous small molecules into novel chemical modalities within cells.

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