期刊
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
卷 143, 期 22, 页码 8454-8464出版社
AMER CHEMICAL SOC
DOI: 10.1021/jacs.1c03035
关键词
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资金
- European Union [754462]
- TASPPI project (H2020-MSCA-ITN-2015) [675179]
- Netherlands Organization for Scientific Research (NWO) [016.150.366, 024.001.035]
The study emphasizes the importance of considering the selectivity of stabilizer molecules in addition to their potency. Targeting the phosphorylated motifs on 14-3-3 hub proteins can lead to the stabilization of specific protein-protein interactions and drive selective PPI stabilization through cooperative complex formation.
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 Pint. 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.
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