9FSJ
Crystal structure of the HECT domain of Smurf 1 in complex with inhibitor 8
Summary for 9FSJ
| Entry DOI | 10.2210/pdb9fsj/pdb |
| Descriptor | E3 ubiquitin-protein ligase SMURF1, ethyl 5-[1,3-benzodioxol-5-ylmethyl(ethyl)carbamoyl]-2,4-dimethyl-1~{H}-pyrrole-3-carboxylate (3 entities in total) |
| Functional Keywords | e3 ubiquitin-protein ligase smurf1, hect domain, inhibitor, allosteric inhibition, bmp signaling, pulmonary vascular remodeling, ligase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 44346.75 |
| Authors | |
| Primary citation | Rothman, A.M.K.,Florentin, A.,Zink, F.,Quigley, C.,Bonneau, O.,Hemmig, R.,Hachey, A.,Rejtar, T.,Thaker, M.,Jain, R.,Huang, S.M.,Sutton, D.,Roger, J.,Zhang, J.H.,Weiler, S.,Cotesta, S.,Ottl, J.,Srivastava, S.,Kordonsky, A.,Avishid, R.,Yariv, E.,Rathi, R.,Khvalevsky, O.,Troxler, T.,Binmahfooz, S.K.,Kleifeld, O.,Morrell, N.W.,Humbert, M.,Thomas, M.J.,Jarai, G.,Beckwith, R.E.J.,Cobb, J.S.,Smith, N.,Ostermann, N.,Tallarico, J.,Shaw, D.,Guth-Gundel, S.,Prag, G.,Rowlands, D.J. Therapeutic potential of allosteric HECT E3 ligase inhibition. Cell, 2025 Cited by 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 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. PubMed: 40179885DOI: 10.1016/j.cell.2025.03.001 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.05 Å) |
Structure validation
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