Genes are the genetic information that defines who and what we are at the cellular level. The ability to turn genes on or off can determine the fate of a cell. With this award, the Chemistry of Life Processes Program in the Chemistry Division, with cofounding from the Genetic Mechanisms Program in the Division of Molecular and Cellular Biosciences is supporting Dr. Angela Koehler from the Massachusetts Institute of Technology. Dr. Koehler is designing and synthesizing new chemical compounds that can change the "master program" that turns genes on and off in a cell. One such compound acts as a molecular glue that holds two molecules of a gene regulator together and, in doing so, turns off a set of genes that have been implicated in human disease. The studies in this project capture atomic level snapshots of the genes and complex together. These pictures allow the design of new molecules that can serve as stronger molecular glues. The results from these studies may provide researchers with molecular tools to reprogram cells and change their activity. The research program is integrated with an education plan to train graduate students and visiting undergraduates (including those from groups that are under-represented in STEM) in advanced biochemical methods. These methods include X-ray crystallography (used to develop atomic pictures of molecules), computer modeling (to help design new molecules), and chemical synthesis (to create the newly designed molecular glues). Dr. Koehler participates in the Broad Institute Summer Research Program, which provides research opportunities to students from under-represented groups from various colleges and universities. She leads an outreach project to develop an interactive game and coloring books as resources to teach the concepts of "good" and "bad" molecular interactions (through analogies to comic book type characters) at the K-12 level. The research group also participates in the Cambridge Science Festival Cancer Program at the Boston Museum of Science, in which the concepts of small molecule-protein binding are presented through analogy to interactions among people.
This research project applies chemical approaches to reprogram gene expression networks by targeting master regulator transcription factors. Molecular compounds that reprogram transcription and alter the fate of cells are tools in synthetic biology, and facilitate the study of cellular development or causes of human disease. The focus of this project is to design molecular compounds that act as glues that can stabilize the repressive homodimeric form of the MAX transcription factor. A published chemical probe (KI-MS2-008) that binds to and stabilizes MAX serves a starting point for structure-guided design of new molecular glues with different chemical core scaffolds. The crystal structure of KI-MS2-008 with MAX elucidates details for how this asymmetric binder stabilizes the homodimeric protein. Structures of the MAX/KI-MS2-008 complex in the presence or absence of DNA guides the design of new molecular glue chemotypes with improved chemical properties and enhanced cellular activity. These new chemotypes are characterized for their effects on the binding of MAX to chromatin and subsequent effects on global patterns of transcriptional activity. General principles resulting from this study aid in the development of molecular glues for other transcriptional homodimers. The project provides graduate students and visiting undergraduates from under-represented groups with opportunities to acquire specialized training in X-ray crystallography, molecular modeling, and synthetic chemistry. The project also contributes to a module in an undergraduate lab course focused on cutting-edge methods in molecular-level engineering of protein interactions and perturbation of cellular systems. Finally, the project forms the basis of a "small molecule detectives" effort for K-12 students interested in perturbing cellular systems.
This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.
