Research

Our research interests focus primarily on the roles of membrane proteins in human health and disease, with a particular interest in membrane proteins with therapeutic potential. Membrane proteins, as a class, make up the majority of therapeutic targets and play essential roles in biology and pathophysiology. We investigate the structure, dynamics, and function of this class of proteins with an interdisciplinary approach synthesizing the output from multiple disparate techniques which allows us to tackle challenging yet biomedically relevant problems. Our lab also has interest in fundamental questions related to structural synthetic biology.  Our investigations focus on the following themes:

1) TRP channel gating and modulation. TRPM8 functions as the primary cold sensor in humans where it integrates, thermo-, chemical-, and voltage-dependencies and is modulated by other proteins and lipids. This channel has significant therapeutic potential in diverse and important diseases such as cancer, chronic pain, obesity, and diabetes. We seek to understand the mechanism of how TRPM8 integrates distinct stimuli and modulators in an effort to unlock the therapeutic potential of TRPM8.

2) Structural synthetic biology. Our lab focuses on two general areas related to synthetic biology. The first is the structural characterization of threose nucleic acid (TNA). TNA has been proposed as a precursor nucleic acid to DNA and RNA. We seek to better characterize the structural attributes of TNA; especially in the context of evolved TNA aptamers and TNA-based enzymes. The second area deals with understanding the genesis of protein folds and their differentiation.

3) Membrane protein structural enzymology. Our lab focuses on two membrane enzymes; vitamin K epoxide reductase (VKOR) and undecaprenol kinase (UDPK). VKOR is the target of the popular anticoagulant warfarin (also Coumadin®) and is one of the hallmark targets of personalized medicine. Undecaprenol kinase is a known virulence factor in gram-positive bacteria and an excellent target for narrow spectrum antibiotic development. For these enzymes we seek to understand the relationship between structure, function, and dynamics.

4) Methods Development for membrane protein structural biology. In an effort to push the boundaries of membrane protein structural biology, we are exploring the use of new, and fine-tuning existing membrane mimics that are compatible with solution NMR. Of particular interest is optimizing reverse micelles as hosts for membrane proteins which have the particular advantage of significantly increasing the size and complexity of NMR-accessible membrane targets.

To accomplish these goals, our research program relies on a number of interdisciplinary techniques including nuclear magnetic resonance spectroscopy (NMR), electrophysiology, enzymology, and computational structural biology.