Structure-guided design of peptides as tools to probe the protein-protein interaction between Cullin-2 and Elongin BC substrate adaptor in Cullin RING E3 ubiquitin ligases

Teresa Cardote, Alessio Ciulli (Lead / Corresponding author)

Research output: Contribution to journalArticlepeer-review

8 Citations (Scopus)
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Abstract

Cullin RING E3 ubiquitin ligases (CRLs) are large dynamic multi-subunit complexes that control the fate of many proteins in cells. CRLs constitute attractive drug targets for the development of small-molecule inhibitors and chemical inducers of protein degradation. Here we describe a structure-guided biophysical approach to probe the protein-protein interaction (PPI) between the Cullin-2 scaffold protein and the adaptor subunits Elongin BC within the context of the von Hippel-Lindau complex (CRL2VHL) using peptides. Two peptides were shown to bind at the targeted binding site on Elongin C, named the “EloC site”, with micromolar dissociation constants, providing a starting point for future optimization. Our results suggest ligandability of the EloC binding site to short linear peptides, unveiling the opportunity and challenges to develop small molecules that have the potential to target selectively the Cul2-adaptor PPI within CRLs.
Original languageEnglish
Pages (from-to)1491-1496
Number of pages6
JournalChemMedChem
Volume12
Issue number18
Early online date3 Aug 2017
DOIs
Publication statusPublished - 21 Sept 2017

Keywords

  • chemical probes
  • Cullin RING E3 ligases
  • peptides
  • protein-protein interactions
  • structure-guided design

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