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Structural basis of PROTAC cooperative recognition for selective protein degradation

DOI: 10.1038/nchembio.2329 DOI Help

Authors: Morgan S. Gadd (University of Dundee) , Andrea Testa (University of Dundee) , Xavier Lucas (University of Dundee) , Kwok-ho Chan (University of Dundee) , Wenzhang Chen (University of Dundee) , Douglas J Lamont (University of Dundee) , Michael Zengerle (University of Dundee) , Alessio Ciulli (University of Dundee)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature Chemical Biology , VOL 7

State: Published (Approved)
Published: March 2017
Diamond Proposal Number(s): 10071 , 14980

Abstract: Inducing macromolecular interactions with small molecules to activate cellular signaling is a challenging goal. PROTACs (proteolysis-targeting chimeras) 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 ligase–PROTAC–target species and its impact on target degradation selectivity remain 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 a stable and cooperative complex with an E3 ligase for selective degradation.

Subject Areas: Chemistry

Instruments: I04-1-Macromolecular Crystallography (fixed wavelength)