Much of the assembly process of the transcription machinery is governed by transient and dynamic protein- protein interactions (PPIs) that defy standard characterization strategies. Transcriptional coactivators are the hubs of this process, interacting with transcriptional activators, epigenetic modulators, the polymerase, and other coactivators to assemble the transcriptional machine. Coactivators also represent a central molecular recognition conundrum, as the mechanisms by which they interact with such a diverse array with binding partners and the influence of local binding interactions on longer-range structural and functional trajectories. In the previous funding period, we developed a molecular recognition model that addresses the first part of the conundrum. Here will build on this model to discover allosteric modulators of coactivators previously labelled undruggable despite their central functional roles. Additionally, we will answer the latter half of the conundrum to develop a comprehensive model of molecular recognition in transcriptional coactivator function.
Transcription is dysregulated in every human disease as either a cause or an effect and as such represents a potentially powerful intervention point for therapeutics; a significant impediment to progress are the many questions regarding the complex network of protein-protein interactions that regulates this process. In this research plan we implement a combination of chemical biology tools and approaches to define key binding interactions and conformational changes that produce function in vitro and in cells. In doing so, we will discover new opportunities for drug discovery, with a particular focus on transcriptional pathways integral to metabolic disease and cancer.
