7ZMW
14-3-3s binding to non-natural peptide 2c
Summary for 7ZMW
| Entry DOI | 10.2210/pdb7zmw/pdb |
| Descriptor | 14-3-3 protein sigma, non-natural peptide 1, MAGNESIUM ION, ... (4 entities in total) |
| Functional Keywords | 14-3-3, non-natural peptide, peptide binding protein |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 2 |
| Total formula weight | 27614.50 |
| Authors | Somsen, B.A.,Craenmehr, F.W.B.,Ottmann, C. (deposition date: 2022-04-19, release date: 2022-11-23, Last modification date: 2024-01-31) |
| Primary citation | Somsen, B.A.,Craenmehr, F.W.B.,Liu, W.W.,Koops, A.A.,Pennings, M.A.M.,Visser, E.J.,Ottmann, C.,Cossar, P.J.,Brunsveld, L. Functional mapping of the 14-3-3 hub protein as a guide to design 14-3-3 molecular glues. Chem Sci, 13:13122-13131, 2022 Cited by PubMed Abstract: Molecular glues represent an evolution in drug discovery, however, targeted stabilization of protein complexes remains challenging, owing to a paucity of drug design rules. The functional mapping of hotspots has been critical to protein-protein interaction (PPI) inhibitor research, however, the orthogonal approach to stabilize PPIs has not exploited this information. Utilizing the hub protein 14-3-3 as a case study we demonstrate that functional mapping of hotspots provides a triage map for 14-3-3 molecular glue development. Truncation and mutation studies allowed deconvoluting the energetic contributions of sidechain and backbone interactions of a 14-3-3-binding non-natural peptide. Three central 14-3-3 hotspots were identified and their thermodynamic characteristics profiled. In addition to the phospho-binding pocket; (i) Asn226, (ii) Lys122 and (iii) the hydrophobic patch formed by Leu218, Ile219 and Leu222 were critical for protein complex formation. Exploiting this hotspot information allowed a peptide-based molecular glue that elicits high cooperativity ( = 36) and selectively stabilizes the 14-3-3/ChREBP PPI to be uniquely developed. PubMed: 36425501DOI: 10.1039/d2sc04662h PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.8 Å) |
Structure validation
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