Two ligandable pockets on the surface of the VHL E3 ligase are revealed in our new paper just out in J Med Chem
- Fragment screening and Xray crystallographic soaking identified two novel pockets – one on VHL far from the HIF site, and one on adaptor subunit ElonginB – both of functional relevance
- Surprisingly we found no fragments bound at the Hydroxyproline site where VHL inhibitors and ligands for PROTACs bind
- The two new pockets were validated computationally using surface probing druggability techniques and solvent MD mapping, and identified other pockets found to bind solvent molecules crystallographically
- The identified sites and non-covalent interactions will guide the design of more potent ligands, which have potential as new E3 ligase binding handles for targeted protein degradation-
Well done to Xavi and Inge!