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.
Molecular glues are powerful tools for the control of protein-protein interactions. Yet, the mechanisms underlying multi-component protein complex formation remain poorly understood. Native mass spectrometry (MS) detects multiple protein species...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.