6YQ2

14-3-3 sigma with RelA/p65 binding site pS45 and covalently bound TCF521-129

Summary for 6YQ2

• Entry DOI: 10.2210/pdb6yq2/pdb
• Related: 6QHL
• Descriptor: 14-3-3 protein sigma, p65pS45, 4-[(2~{R},6~{S})-2,6-dimethylmorpholin-4-yl]sulfonylbenzaldehyde, ... (4 entities in total)
• Functional Keywords: covalent fragment, p65, 1433, peptide binding protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 28254.69

Authors

Wolter, M.,Ottmann, C. (deposition date: 2020-04-16, release date: 2020-09-23, Last modification date: 2024-10-16)

Primary citation

Wolter, M.,Valenti, D.,Cossar, P.J.,Levy, L.M.,Hristeva, S.,Genski, T.,Hoffmann, T.,Brunsveld, L.,Tzalis, D.,Ottmann, C.
Fragment-Based Stabilizers of Protein-Protein Interactions through Imine-Based Tethering.
Angew.Chem.Int.Ed.Engl., 59:21520-21524, 2020

PubMed Abstract: Small-molecule stabilization of protein-protein interactions (PPIs) is a promising concept in drug discovery, however the question how to identify or design chemical starting points in a "bottom-up" approach is largely unanswered. We report a novel concept for identifying initial chemical matter for PPI stabilization based on imine-forming fragments. The imine bond offers a covalent anchor for site-directed fragment targeting, whereas its transient nature enables efficient analysis of structure-activity relationships. This bond enables fragment identification and optimisation using protein crystallography. We report novel fragments that bind specifically to a lysine at the PPI interface of the p65-subunit-derived peptide of NF-κB with the adapter protein 14-3-3. Those fragments that subsequently establish contacts with the p65-derived peptide, rather than with 14-3-3, efficiently stabilize the 14-3-3/p65 complex and offer novel starting points for molecular glues.

PubMed: 32816380
DOI: 10.1002/anie.202008585

Experimental method

X-RAY DIFFRACTION (1.4 Å)