Friday, January 30, 2015; 3:00 p.m.; Chem 200 (Kobilka Lecture Hall)
Department of Chemistry & Biochemistry Welcomes:
Dr. William Pomerantz
Assistant Professor, Department of Chemistry, University of Minnesota Twin Cities
“Aromatic Amino Acids: Privileged Side-Chains For Small Molecule Discovery”
In this talk, I will describe our recent results developing small molecule screening methods to discover organic molecules for modulating gene regulation by transcription factors. 19F NMR of labeled proteins is a sensitive method for characterizing structure, conformational dynamics, higher-order assembly, and ligand binding. We previously reported an application of our method to study the transcription factor domain KIX and have since screened over 500 compounds. Here, I will describe a 19F NMR method for detecting bromodomain-ligand interactions using fluorine-labeled aromatic amino acids due to the high conservation of aromatic residues in the bromodomain binding site. We test the sensitivity, accuracy, and speed of this method with known small molecule inhibitors using three different bromodomains Brd4, BrdT and BPTF. Simultaneous testing of multiple bromodomains and has led to the discovery of several selective ligands. Fluorine labeling only modestly affected protein structure and function assessed by isothermal titration calorimetry, circular dichroism, and x-ray crystallography. The speed, ease of interpretation, and low concentration of protein needed for binding experiments affords a new method to discover and characterize both native and new ligands for bromodomains and may find utility in the study of additional epigenetic “reader” domains.