7bg3

Publication Abstract from PubMed

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 de novo 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.

Reversible Covalent Imine-Tethering for Selective Stabilization of 14-3-3 Hub Protein Interactions.,Cossar PJ, Wolter M, van Dijck L, Valenti D, Levy LM, Ottmann C, Brunsveld L J Am Chem Soc. 2021 Jun 9;143(22):8454-8464. doi: 10.1021/jacs.1c03035. Epub 2021 , May 28. PMID:34047554^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.