5T35
The PROTAC MZ1 in complex with the second bromodomain of Brd4 and pVHL:ElonginC:ElonginB
Summary for 5T35
| Entry DOI | 10.2210/pdb5t35/pdb |
| Descriptor | Bromodomain-containing protein 4, Transcription elongation factor B polypeptide 2, Transcription elongation factor B polypeptide 1, ... (6 entities in total) |
| Functional Keywords | protac complex, targeted degradation, chromatin reader, ubiquitin ligase, bifunctional ligand, ligase |
| Biological source | Homo sapiens (Human) More |
| Cellular location | Nucleus: O60885 Q15370 Q15369 Isoform 1: Cytoplasm. Isoform 3: Cytoplasm: P40337 |
| Total number of polymer chains | 8 |
| Total formula weight | 114980.60 |
| Authors | Gadd, M.S.,Zengerle, M.,Ciulli, A. (deposition date: 2016-08-24, release date: 2017-03-08, Last modification date: 2024-01-17) |
| Primary citation | Gadd, M.S.,Testa, A.,Lucas, X.,Chan, K.H.,Chen, W.,Lamont, D.J.,Zengerle, M.,Ciulli, A. Structural basis of PROTAC cooperative recognition for selective protein degradation. Nat. Chem. Biol., 13:514-521, 2017 Cited by PubMed 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 (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. PubMed: 28288108DOI: 10.1038/nchembio.2329 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.7 Å) |
Structure validation
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