Rational Screening for Cooperativity in Small-Molecule Inducers of Protein-Protein Associations.

ABSTRACT: The hallmark of a molecular glue is its ability to induce cooperative protein-protein interactions, leading to the formation of a ternary complex, despite weaker binding toward one or both individual proteins. Notably, the extent of cooperativity distinguishes molecular glues from bifunctional compounds, which constitute a second class of inducers of protein-protein interactions. However, apart from serendipitous discovery, there have been limited rational screening strategies for the high cooperativity exhibited by molecular glues. Here, we propose a binding-based screen of DNA-barcoded compounds on a target protein in the presence or absence of a presenter protein, using the "presenter ratio", the ratio of ternary enrichment to binary enrichment, as a predictive measure of cooperativity.

SUBMITTER: Liu S 

PROVIDER: S-EPMC10603787 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature