Supplemental proteomics data Abstract: Inhibition of ubiquitin E3-ligases is therapeutically attractive; however, the absence of an active-site pocket impedes computational approaches to inhibitor identification. In a large unbiased physical screen, we discovered inhibitors that bind a cryptic cavity distant from the protruding SMURF1 catalytic cysteine. Structural and biochemical analyses, and engineered escape mutants, revealed that the inhibitors restrict an essential catalytic motion by extending an α-helix over a conserved glycine-hinge. SMURF1 is overexpressed in patients with pulmonary arterial hypertension (PAH), a disease caused by mutation of bone morphogenetic protein receptor-2 (BMPR2). We demonstrated that SMURF1 inhibition prevents direct BMPR2 ubiquitylation, normalizes BMP-signaling, restores pulmonary vascular cell homeostasis and reverses pathology in established, experimental PAH. We leveraged this deep mechanistic understanding to undertake a machine learning-based screen that identified inhibitors of the prototypic HECT E6AP, and confirm glycine-hinge-dependent allosteric activity. Inhibition of HECT E3s and other glycine-hinge proteins opens a new druggable space.