9fsh | pdb_00009fsh
Crystal structure of the HECT domain of Smurf 2 in complex with inhibitor 8
Structural highlights
FunctionSMUF2_HUMAN E3 ubiquitin-protein ligase which accepts ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates. Interacts with SMAD1 and SMAD7 in order to trigger their ubiquitination and proteasome-dependent degradation. In addition, interaction with SMAD7 activates autocatalytic degradation, which is prevented by interaction with SCYE1. Forms a stable complex with the TGF-beta receptor-mediated phosphorylated SMAD2 and SMAD3. In this way, SMAD2 may recruit substrates, such as SNON, for ubiquitin-mediated degradation. Enhances the inhibitory activity of SMAD7 and reduces the transcriptional activity of SMAD2. Coexpression of SMURF2 with SMAD1 results in considerable decrease in steady-state level of SMAD1 protein and a smaller decrease of SMAD2 level.[1] [2] Publication Abstract from PubMedTargeting 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 alpha 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. Therapeutic potential of allosteric HECT E3 ligase inhibition.,Rothman AMK, Florentin A, Zink F, Quigley C, Bonneau O, Hemmig R, Hachey A, Rejtar T, Thaker M, Jain R, Huang SM, Sutton D, Roger J, Zhang JH, Weiler S, Cotesta S, Ottl J, Srivastava S, Kordonsky A, Avishid R, Yariv E, Rathi R, Khvalevsky O, Troxler T, Binmahfooz SK, Kleifeld O, Morrell NW, Humbert M, Thomas MJ, Jarai G, Beckwith REJ, Cobb JS, Smith N, Ostermann N, Tallarico J, Shaw D, Guth-Gundel S, Prag G, Rowlands DJ Cell. 2025 Apr 2:S0092-8674(25)00274-0. doi: 10.1016/j.cell.2025.03.001. PMID:40179885[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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