Cambridge Cardiovascular Seminar Series- January 2026

Alex Rothman, Professor of Cardiology and Honorary Consultant Cardiologist, The University of Sheffield and Sheffield Teaching Hospital NHS Foundation Trust 

A novel allosteric mechanism of HECT E3 ligase inhibition – targeting the glycine hinge of SMURF1 to treat pulmonary arterial hypertension

Abstract 

Ubiquitin E3 ligases are attractive therapeutic targets, but the absence of an active-site pocket limits structure-based drug discovery. Using a large, unbiased biochemical screen, small-molecule inhibitors of the HECT E3 ligase SMURF1 were identified, that engage a cryptic allosteric cavity, restricting a critical catalytic motion through stabilization of an α-helix over a conserved glycine hinge. SMURF1 levels are elevated in pulmonary arterial hypertension (PAH), where BMPR2 mutations disrupt BMP signaling to cause disease. SMURF1 inhibition prevented direct ubiquitylation of BMPR2 and downstream signaling mediators to restore BMP pathway activity, re-establish pulmonary vascular cell homeostasis, and reverse disease in experimental models. With understanding of the mechanism of inhibition a machine-learning, in silico screen identified inhibitors of the prototypic HECT ligase E6AP, confirming glycine-hinge-dependent allosteric activity in vitro. Inhibiting HECTs and other glycine-hinge proteins opens a new druggable space.

Alex Rothman will be available before and after his presentation. Please contact Mark Toshner if you would like to arrange a meeting

A light lunch will be provided from 12.30 pm

It would be great to see you in person, but if you need to attend remotely please contact Sarah Gibings to receive a Teams link