7AXN

14-3-3 sigma in complex with Pin1 binding site pS72 and covalently bound TCF521-026

Summary for 7AXN

• Entry DOI: 10.2210/pdb7axn/pdb
• Related: 7AOG
• Descriptor: 14-3-3 protein sigma, Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1, 3-chloranyl-4-imidazol-1-yl-benzaldehyde, ... (6 entities in total)
• Functional Keywords: 1433, peptide binding protein, peptidyl-prolyl cis-trans isomerase nima-interacting 1
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 30826.31

Authors

Wolter, M.,Dijck, L.v.,Ottmann, C. (deposition date: 2020-11-10, release date: 2021-06-16, Last modification date: 2024-10-23)

Primary citation

Cossar, P.J.,Wolter, M.,van Dijck, L.,Valenti, D.,Levy, L.M.,Ottmann, C.,Brunsveld, L.
Reversible Covalent Imine-Tethering for Selective Stabilization of 14-3-3 Hub Protein Interactions.
J.Am.Chem.Soc., 143:8454-8464, 2021

PubMed Abstract: The stabilization of protein complexes has emerged as a promising modality, expanding the number of entry points for novel therapeutic intervention. Targeting proteins that mediate protein-protein interactions (PPIs), such as hub proteins, is equally challenging and rewarding as they offer an intervention platform for a variety of diseases, due to their large interactome. 14-3-3 hub proteins bind phosphorylated motifs of their interaction partners in a conserved binding channel. The 14-3-3 PPI interface is consequently only diversified by its different interaction partners. Therefore, it is essential to consider, additionally to the potency, also the selectivity of stabilizer molecules. Targeting a lysine residue at the interface of the composite 14-3-3 complex, which can be targeted explicitly via aldimine-forming fragments, we studied the design of PPI stabilizers under consideration of potential selectivity. By applying cooperativity analysis of ternary complex formation, we developed a reversible covalent molecular glue for the 14-3-3/Pin1 interaction. This small fragment led to a more than 250-fold stabilization of the 14-3-3/Pin1 interaction by selective interfacing with a unique tryptophan in Pin1. This study illustrates how cooperative complex formation drives selective PPI stabilization. Further, it highlights how specific interactions within a hub proteins interactome can be stabilized over other interactions with a common binding motif.

PubMed: 34047554
DOI: 10.1021/jacs.1c03035

Experimental method

X-RAY DIFFRACTION (1.4 Å)