Protein-protein interfaces in molecular glue-induced ternary complexes: classification, characterization, and prediction

Molecular glues are a class of small molecules that stabilize the interactions between proteins. Naturally occurring molecular glues are present in many areas of biology where they serve as central regulators of signaling pathways. Importantly, several clinical compounds act as molecular glue degraders that stabilize interactions between E3 ubiquitin ligases and target proteins, leading to their degradation. Molecular glues hold promise as a new generation of therapeutic agents, including those molecular glue degraders that can redirect the protein degradation machinery in a precise way. However, rational discovery of molecular glues is difficult in part due to the lack of understanding of the protein-protein interactions they stabilize. In this review, we summarize the structures of known molecular glue-induced ternary complexes and the interface properties. Detailed analysis shows different mechanisms of ternary structure formation. Additionally, we also review computational approaches for predicting protein-protein interfaces and highlight the promises and challenges. This information will ultimately help inform future approaches for rational molecular glue discovery.