Two ligandable pockets on the surface of the VHL E3 ligase are revealed in our new paper just out in J Med Chem

  • Graphical Abstract
  • Figure 1. Fragment-based probing of the VHL:EloC:EloB E3 ubiquitin ligase.
  • Figure 2. Computational surface probing of the VHL:EloC:EloB E3 ligase.
  • Figure 3. Structural analysis of VHL:EloC:EloB E3 ubiquitin ligase sites.
  • 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!

Read our paper Open Access here.