9FSJ

Crystal structure of the HECT domain of Smurf 1 in complex with inhibitor 8

9FSJ の概要

• エントリーDOI: 10.2210/pdb9fsj/pdb
• 分子名称: 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)
• 機能のキーワード: e3 ubiquitin-protein ligase smurf1, hect domain, inhibitor, allosteric inhibition, bmp signaling, pulmonary vascular remodeling, ligase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 44346.75

構造登録者

Ostermann, N. (登録日: 2024-06-21, 公開日: 2025-04-16, 最終更新日: 2025-05-28)

主引用文献

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, 188:2603-, 2025

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: 40179885
DOI: 10.1016/j.cell.2025.03.001

実験手法

X-RAY DIFFRACTION (2.05 Å)