Structural basis of PROTAC cooperative recognition for selective protein degradation

Gadd, Morgan S and Testa, Andrea and Lucas, Xavier and Chan, Kwok-Ho and Chen, Wenzhang and Lamont, Douglas J and Zengerle, Michael and Ciulli, Alessio (2017) Structural basis of PROTAC cooperative recognition for selective protein degradation. Nature Chemical Biology, 13 (5). pp. 514-521. ISSN 1552-4450

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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.

Item Type:
Journal Article
Journal or Publication Title:
Nature Chemical Biology
Uncontrolled Keywords:
?? amino acid sequencecrystallography, x-raydipeptideselonginheterocyclic compounds, 3-ringhumansmodels, molecularmultiprotein complexesnuclear proteinsprotein bindingprotein conformationproteolysissmall molecule librariesstructure-activity relationshiptherm ??
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Deposited On:
19 Dec 2017 13:42
Last Modified:
28 Jun 2024 23:55