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Monday, July 1 • 12:15pm - 12:30pm
Discovery of small molecule binding site hotspots in the global proteome

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All biological processes are governed by chemical signals relayed through protein networks. These small molecule signals can inhibit, enhance, or impart new functions to proteins through direct associations to allosteric regulatory hotspots on a protein that drive alteration of the broader proteomic network.  To discover allosteric hotspots in the global proteome, we developed a chemical proteomics platform termed small molecule interactome mapping by photo-affinity labeling (SIM-PAL).  SIM-PAL uses a small molecule carrying a photo-affinity label to capture molecular interactions within the global proteome.  After treatment of live cells with the small molecule, the resulting interactions are captured by photochemical conjugation.  The small molecule-conjugated proteome is tagged with a cleavable biotin azide probe by copper-mediated azide–alkyne cycloaddition (CuAAC) for affinity enrichment and isotope-recoding.  The enriched proteins are identified by proteomics and the exact binding sites are mapped by isotope-targeted mass spectrometry (MS). Isotope-targeted MS enables the selection of small molecule-linked peptides against a background of unlabeled peptides for high-confidence identification of the underlying molecular structure.  SIM-PAL combines phenotypic cellular assays with high-resolution structural measurement of where and when a small molecule is binding throughout the whole proteome using the discovery power of MS.  Applications of SIM-PAL to bioactive small molecules and the structural implications of binding site hotspots from photo-affinity labeling chemistry will be described.

avatar for Christina Woo, PhD

Christina Woo, PhD

Assistant Professor, Harvard University
Christina M. Woo is an assistant professor in the Department of Chemistry and Chemical Biology at Harvard University, and an affiliate member of the Broad Institute. She obtained a BA in Chemistry from Wellesley College (2008), and conducted undergraduate research in the laboratory... Read More →

Monday July 1, 2019 12:15pm - 12:30pm EDT
Abigail Adams Salon A/B