Surface probing by fragment-based screening and computational methods identifies ligandable pockets on the von Hippel-Lindau (VHL) E3 ubiquitin ligase

Xavier Lucas, Inge van Molle, Alessio Ciulli (Lead / Corresponding author)

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Abstract

Beyond the targeting of E3 ubiquitin ligases to inhibit protein homeostasis, E3 ligase binders can be repurposed as targeted protein degraders (PROTACs or molecular glues). We sought to identify new binders of the VHL E3 ligase by biophysical fragment-based screening followed by X-ray crystallographic soaking. We identified fragments binding at the ElonginC:Cullin2 interface and a new cryptic pocket in VHL, along with other potential ligandable sites predicted computationally and found to bind solvent molecules in crystal structures. The elucidated interactions provide starting points for future ligand development.

Original languageEnglish
Pages (from-to)7387-7393
Number of pages7
JournalJournal of Medicinal Chemistry
Volume61
Issue number16
Early online date24 Jul 2018
DOIs
Publication statusPublished - 23 Aug 2018

Keywords

  • cryptic pockets
  • VHL
  • Cullin-RING ligase
  • mixed-solvent molecular dynamics
  • ligandability
  • druggability
  • protein-protein interactions
  • solvent mapping
  • PROTAC
  • protein degradation
  • Elongin C
  • Chuvash polycythemia

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