{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Rothman AMK"],"funding":["Wellcome Trust"],"pagination":["2603-2620.e18"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC12087876"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["188(10)"],"pubmed_abstract":["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 "],"journal":["Cell"],"pubmed_title":["Therapeutic potential of allosteric HECT E3 ligase inhibition."],"pmcid":["PMC12087876"],"funding_grant_id":["206632/Z/17/Z"],"pubmed_authors":["Ottl J","Quigley C","Roger J","Sutton D","Shaw D","Binmahfooz SK","Khvalevsky O","Jarai G","Guth-Gundel S","Troxler T","Yariv E","Hemmig R","Avishid R","Thomas MJ","Weiler S","Prag G","Kordonsky A","Thaker M","Huang SM","Florentin A","Bonneau O","Jain R","Rathi R","Cobb JS","Ostermann N","Rejtar T","Zhang JH","Rothman AMK","Morrell NW","Srivastava S","Smith N","Kleifeld O","Cotesta S","Beckwith REJ","Tallarico J","Rowlands DJ","Hachey A","Zink F","Humbert M"],"additional_accession":[]},"is_claimable":false,"name":"Therapeutic potential of allosteric HECT E3 ligase inhibition.","description":"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 ","dates":{"release":"2025-01-01T00:00:00Z","publication":"2025 May","modification":"2026-06-01T06:15:19.159Z","creation":"2026-04-08T09:50:17.93Z"},"accession":"S-EPMC12087876","cross_references":{"pubmed":["40179885"],"doi":["10.1016/j.cell.2025.03.001"]}}