My long-term research interests are centered on understanding transmembrane signaling processes mediated by cell surface receptors such as G protein-coupled receptors, receptor tyrosine kinases, and the T cell receptor. During my tenure in the Sondek lab, I have focused on defining the mechanisms controlling the activity of the phospholipase C (PLC) family of isozymes, specifically PLC-gamma1 (PLC-g1) and PLC-g2. During this time, I have utilized a wide array of biochemical, biophysical, computational, and structural biology techniques to dissect the regulation of these isozymes in contexts ranging from intact cells to high-resolution atomic structures. I have used X-ray crystallography to solve structures of isolated domains from PLC-g1 (Hajicek et al., Biochemistry 2013). Notably, I also determined the first structure of an essentially full-length version of PLC-g1 (Hajicek et al., eLife 2019).
I am currently using the high-resolution X-ray structure of PLC-g1 to perform sophisticated all-atom molecular dynamics simulations of this isozyme in a joint effort with Dr. Brenda Temple. These simulations are designed to: i) model the structural effects of gain-of-function substitutions found in cancers; ii) define interactions between PLC-g1 and small molecules; and iii) model the behavior of this isozyme at membrane surfaces.
