Nature chemical biology, 2017-05, Vol.13 (5), p.514
2017
Details
- Autor(en) / Beteiligte
- Titel
- Structural basis of PROTAC cooperative recognition for selective protein degradation
- Ist Teil von
- Nature chemical biology, 2017-05, Vol.13 (5), p.514
- Ort / Verlag
- United States
- Erscheinungsjahr
- 2017
- Link zum Volltext
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- 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 (Brd4 ). 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 Brd4 . 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.
- Sprache
- Englisch
- Identifikatoren
- eISSN: 1552-4469DOI: 10.1038/nchembio.2329Titel-ID: cdi_pubmed_primary_28288108
- Format
- –
- Schlagworte
- Amino Acid Sequence, Cell Cycle Proteins, Crystallography, X-Ray, Dipeptides - chemistry, Dipeptides - pharmacology, Elongin, Heterocyclic Compounds, 3-Ring - chemistry, Heterocyclic Compounds, 3-Ring - pharmacology, Humans, Models, Molecular, Multiprotein Complexes - chemistry, Multiprotein Complexes - metabolism, Nuclear Proteins - chemistry, Nuclear Proteins - metabolism, Protein Binding, Protein Conformation, Proteolysis - drug effects, Small Molecule Libraries - chemistry, Small Molecule Libraries - pharmacology, Structure-Activity Relationship, Thermodynamics, Transcription Factors - chemistry, Transcription Factors - metabolism, Ubiquitin-Protein Ligases - metabolism, Von Hippel-Lindau Tumor Suppressor Protein - chemistry, Von Hippel-Lindau Tumor Suppressor Protein - metabolism