6RWH

Fragment AZ-007 binding at a primary and secondary binding site of the the p53pT387/14-3-3 sigma complex

Summary for 6RWH

• Entry DOI: 10.2210/pdb6rwh/pdb
• Descriptor: 14-3-3 protein sigma, Cellular tumor antigen p53, 5-(1~{H}-imidazol-5-yl)-4-phenyl-thiophene-2-carboximidamide, ... (6 entities in total)
• Functional Keywords: protein protein interaction, fragment soaking, stabilization, peptide binding protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 30285.40

Authors

Leysen, S.,Guillory, X.,Wolter, M.,Genet, S.,Somsen, B.,Patel, J.,Castaldi, P.,Ottmann, C. (deposition date: 2019-06-05, release date: 2020-06-17, Last modification date: 2024-11-13)

Primary citation

Guillory, X.,Wolter, M.,Leysen, S.,Neves, J.F.,Kuusk, A.,Genet, S.,Somsen, B.,Morrow, J.K.,Rivers, E.,van Beek, L.,Patel, J.,Goodnow, R.,Schoenherr, H.,Fuller, N.,Cao, Q.,Doveston, R.G.,Brunsveld, L.,Arkin, M.R.,Castaldi, P.,Boyd, H.,Landrieu, I.,Chen, H.,Ottmann, C.
Fragment-based Differential Targeting of PPI Stabilizer Interfaces.
J.Med.Chem., 63:6694-6707, 2020

PubMed Abstract: Stabilization of protein-protein interactions (PPIs) holds great potential for therapeutic agents, as illustrated by the successful drugs rapamycin and lenalidomide. However, how such interface-binding molecules can be created in a rational, bottom-up manner is a largely unanswered question. We report here how a fragment-based approach can be used to identify chemical starting points for the development of small-molecule stabilizers that differentiate between two different PPI interfaces of the adapter protein 14-3-3. The fragments discriminately bind to the interface of 14-3-3 with the recognition motif of either the tumor suppressor protein p53 or the oncogenic transcription factor TAZ. This X-ray crystallography driven study shows that the rim of the interface of individual 14-3-3 complexes can be targeted in a differential manner with fragments that represent promising starting points for the development of specific 14-3-3 PPI stabilizers.

PubMed: 32501690
DOI: 10.1021/acs.jmedchem.9b01942

Experimental method

X-RAY DIFFRACTION (1.68 Å)