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Therapeutic potential of allosteric HECT E3 ligase inhibition

AMK. Rothman, A. Florentin, F. Zink, C. Quigley, O. Bonneau, R. Hemmig, A. Hachey, T. Rejtar, M. Thaker, R. Jain, SM. Huang, D. Sutton, J. Roger, JH. Zhang, S. Weiler, S. Cotesta, J. Ottl, S. Srivastava, A. Kordonsky, R. Avishid, E. Yariv, R....

. 2025 ; 188 (10) : 2603-2620.e18. [pub] 20250402

Language English Country United States

Document type Journal Article

Persistent link   https://www.medvik.cz/link/bmc25015735

Targeting ubiquitin E3 ligases is therapeutically attractive; however, the absence of an active-site pocket impedes computational approaches for identifying inhibitors. In a large, unbiased biochemical screen, we discover inhibitors that bind a cryptic cavity distant from the catalytic cysteine of the homologous to E6-associated protein C terminus domain (HECT) E3 ligase, SMAD ubiquitin regulatory factor 1 (SMURF1). Structural and biochemical analyses and engineered escape mutants revealed that these inhibitors restrict an essential catalytic motion by extending an α helix over a conserved glycine hinge. SMURF1 levels are increased in pulmonary arterial hypertension (PAH), a disease caused by mutation of bone morphogenetic protein receptor-2 (BMPR2). We demonstrated that SMURF1 inhibition prevented BMPR2 ubiquitylation, normalized bone morphogenetic protein (BMP) signaling, restored pulmonary vascular cell homeostasis, and reversed pathology in established experimental PAH. Leveraging this deep mechanistic understanding, we undertook an in silico machine-learning-based screen to identify inhibitors of the prototypic HECT E6AP and confirmed glycine-hinge-dependent allosteric activity in vitro. Inhibiting HECTs and other glycine-hinge proteins opens a new druggable space.

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$a Therapeutic potential of allosteric HECT E3 ligase inhibition / $c AMK. Rothman, A. Florentin, F. Zink, C. Quigley, O. Bonneau, R. Hemmig, A. Hachey, T. Rejtar, M. Thaker, R. Jain, SM. Huang, D. Sutton, J. Roger, JH. Zhang, S. Weiler, S. Cotesta, J. Ottl, S. Srivastava, A. Kordonsky, R. Avishid, E. Yariv, R. Rathi, O. Khvalevsky, T. Troxler, SK. Binmahfooz, O. Kleifeld, NW. Morrell, M. Humbert, MJ. Thomas, G. Jarai, REJ. Beckwith, JS. Cobb, N. Smith, N. Ostermann, J. Tallarico, D. Shaw, S. Guth-Gundel, G. Prag, DJ. Rowlands
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$a Florentin, Amir $u School of Neurobiology, Biochemistry and Biophysics, The Life Sciences Faculty, Tel Aviv University, Tel Aviv, Israel
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$a Binmahfooz, Sarah K $u University of Sheffield, Sheffield, UK; Department of Clinical Biochemistry, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
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$a Kleifeld, Oded $u Faculty of Biology, Technion-Israel Institute of Technology, Haifa 32000, Israel
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$a Morrell, Nicholas W $u Department of Medicine, School of Clinical Medicine, University of Cambridge, Cambridge, UK
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$a Humbert, Marc $u Université Paris-Saclay, INSERM UMR_S 999 (HPPIT), Service de Pneumologie et Soins Intensifs Respiratoires, Hôpital Bicêtre (Assistance Publique Hôpitaux de Paris), Le Kremlin Bicêtre, France
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$a Thomas, Matthew J $u Novartis Institutes for BioMedical Research (NIBR), Horsham, UK
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$a Shaw, Duncan $u Novartis BioMedical Research (NBR), Cambridge, MA, USA
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$a Prag, Gali $u School of Neurobiology, Biochemistry and Biophysics, The Life Sciences Faculty, Tel Aviv University, Tel Aviv, Israel; Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel. Electronic address: prag@tauex.tau.ac.il
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