7BKH

14-3-3 sigma with RelA/p65 binding site pS45 and covalently bound TCF521-153

Summary for 7BKH

• Entry DOI: 10.2210/pdb7bkh/pdb
• Related: 6QHL
• Descriptor: 14-3-3 protein sigma, Transcription factor p65, 4-nitro-3-[(3S)-3-oxidanylpiperidin-1-yl]benzaldehyde, ... (4 entities in total)
• Functional Keywords: benzaldehyde, covalent fragment, p65, 1433, rela, peptide binding protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 30139.45

Authors

Wolter, M.,Ottmann, C. (deposition date: 2021-01-16, release date: 2021-06-09, Last modification date: 2024-10-16)

Primary citation

Wolter, M.,Valenti, D.,Cossar, P.J.,Hristeva, S.,Levy, L.M.,Genski, T.,Hoffmann, T.,Brunsveld, L.,Tzalis, D.,Ottmann, C.
An Exploration of Chemical Properties Required for Cooperative Stabilization of the 14-3-3 Interaction with NF-kappa B-Utilizing a Reversible Covalent Tethering Approach.
J.Med.Chem., 64:8423-8436, 2021

PubMed Abstract: Protein-protein modulation has emerged as a proven approach to drug discovery. While significant progress has been gained in developing protein-protein interaction (PPI) inhibitors, the orthogonal approach of PPI stabilization lacks established methodologies for drug design. Here, we report the systematic ″bottom-up″ development of a reversible covalent PPI stabilizer. An imine bond was employed to anchor the stabilizer at the interface of the 14-3-3/p65 complex, leading to a molecular glue that elicited an 81-fold increase in complex stabilization. Utilizing protein crystallography and biophysical assays, we deconvoluted how chemical properties of a stabilizer translate to structural changes in the ternary 14-3-3/p65/molecular glue complex. Furthermore, we explore how this leads to high cooperativity and increased stability of the complex.

PubMed: 34076416
DOI: 10.1021/acs.jmedchem.1c00401

Experimental method

X-RAY DIFFRACTION (1.4 Å)