A central theme of my research is Ca2+ regulation and cAMP mediated cell signaling in cardiac and skeletal muscle. Both soluble and integral membrane proteins orchestrate these biological events. To characterize these large macromolecules involved in these signaling and transport mechanisms, my group utilizes an interdisciplinary approach that includes several chemical and biophysical tools. A major emphasis of my research is correlating the conformational dynamics (motions) of macromolecules to their function and dysfunction in living organisms. We use recombinant DNA techniques to express and purify isotopically labeled proteins using E. coli vectors. These proteins and protein-protein complexes are then reconstituted under near-physiological conditions and studied by spectroscopic techniques.
Soluble proteins are studied by solution-state NMR approaches, while membrane proteins are reconstituted in lipid membranes and analyzed using solid-state NMR techniques. Specifically, we have implemented a hybrid NMR approach that utilizes both magic angle spinning (MAS) and oriented solid-state NMR techniques to determine both the structure and topology of membrane proteins. We continue to build on our successful structure determination of several small and medium size membrane proteins to understand how the transmission of signaling events across the membrane via protein-protein complexes functions in cellular regulation and disease states.
We are also interested in understanding how molecular motions influence enzymatic turnover. To this extent, we use NMR spin relaxation techniques to study enzymes’ conformational dynamics with atomic resolution using a multi-timescale approach, correlating our experimental data with atomistic molecular dynamics simulations. Our goal is to map pathways for allosteric regulation in enzymes, such as protein kinase A (PKA), for the future design of small molecules to fine-tune enzymes’ function.
Honors and Awards
National Institute of Health Career Award, 2005
38th Eastern Analytical Symposium Prize, 1999
University of Minnesota
Department of Chemistry
A-11, 139 Smith Hall
207 Pleasant St SE
Minneapolis, MN 55455-0431