Structural basis of PROTAC cooperative recognition for selective protein degradation

Morgan Gadd, Andrea Testa, Xavier Lucas, Kwok Ho Chan, Wenzhang Chen, Douglas Lamont, Michael Zengerle, Alessio Ciulli (Lead / Corresponding author)

Research output: Contribution to journalArticlepeer-review

246 Citations (Scopus)
379 Downloads (Pure)

Abstract

Inducing macromolecular interactions with small molecules to activate cellular signaling is a challenging goal. PROTACs (proteolysis-targeting chimaeras) are bifunctional molecules that recruit a target protein in proximity to an E3 ubiquitin ligase to trigger protein degradation. Structural elucidation of the key ternary species ligase:PROTAC:target and how this impacts target degradation selectivity remains elusive. We solved the crystal structure of Brd4-degrader MZ1 in complex with human VHL and the Brd4 bromodomain (Brd4BD2). The ligand folds into itself to allow formation of specific intermolecular interactions in the ternary complex. Isothermal titration calorimetry studies, supported by surface mutagenesis and proximity assays, are consistent with pronounced cooperative formation of ternary complexes with Brd4BD2. Structure-based designed compound AT1 exhibits highly selective depletion of Brd4 in cells. Our results elucidate how PROTAC-induced de novo contacts dictate preferential recruitment of a target protein into stable and cooperative complex with an E3 ligase for selective degradation.
Original languageEnglish
Pages (from-to)514-521
Number of pages11
JournalNature Chemical Biology
Volume13
Issue number5
Early online date13 Mar 2017
DOIs
Publication statusPublished - May 2017

Keywords

  • Biophysics
  • Pharmacology
  • Small molecules
  • X-ray crystallography

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