Reversible Covalent Imine-Tethering for Selective Stabilization of 14-3-3 Hub Protein Interactions
Peter J. Cossar, M. Wolter, L.v. Dijck, Dario Valenti, Laura M. Levy, Christian Ottmann, Luc Brunsveld
Abstract
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.
Topics & Concepts
ChemistryInteractomeProtein–protein interactionAllosteric regulationSmall moleculeCooperativityPlasma protein bindingCooperative bindingCovalent bondCombinatorial chemistryFKBPBiophysicsBinding siteStereochemistryBiochemistryReceptorBiologyOrganic chemistryGene14-3-3 protein interactionsUbiquitin and proteasome pathwaysSignaling Pathways in Disease