Engineering selective competitors for the discrimination of highly conserved protein-protein interaction modules.

ABSTRACT: Designing highly specific modulators of protein-protein interactions (PPIs) is especially challenging in the context of multiple paralogs and conserved interaction surfaces. In this case, direct generation of selective and competitive inhibitors is hindered by high similarity within the evolutionary-related protein interfaces. We report here a strategy that uses a semi-rational approach to separate the modulator design into two functional parts. We first achieve specificity toward a region outside of the interface by using phage display selection coupled with molecular and cellular validation. Highly selective competition is then generated by appending the more degenerate interaction peptide to contact the target interface. We apply this approach to specifically bind a single PDZ domain wi

SUBMITTER: Rimbault C 

PROVIDER: S-EPMC6778148 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature