Professor Physiology and Biophysics, Biochemistry and Molecular Biology
- Transport protein biophysics
- Na, K-ATPase
- Neurotransmitter transport
- Peptide transport
- Ion Channels
- Protein structure
- Membrane proteins
- Molecular dynamics simulations
Research OverviewThe primary interest of our lab is to understand the mechanisms that cells have developed to move ions and small molecules across cell membranes. Ion gradients of sodium and potassium underlie all electrical activity in cells, and in one project we are concerned with the structure and mechanism of Na,K-ATPase, the protein that catalyzes the active transport of these ions and establishes and maintains their transmembrane electrochemical potential gradients. In another line of investigation, we are studying the mechanisms of serotonin and GABA transport by neuronal serotonin and GABA transporters. These transporters are members of a class of proteins that couple neurotransmitter uptake to the transport of sodium ions, and often other ions as well, and we are working to understand how interactions among these different substrates and the proteins lead to their transport. The serotonin transporter, in particular, also exhibits characteristics of both an alternating access transporter and an ion channel, and we are interested to know how this observation can be explained. A third area of interest in our lab is the transport of small peptides across the intestinal epithelium. The transporter for these peptides, PepT1, recognizes and transports all combinations of di- and tri-peptides, but does not transport individual amino acids. Because PepT1 also transports certain peptide-drug conjugates and some small antibiotics, it is an attractive target for prodrug development designed to facilitate the convenient oral delivery of pharmaceuticals.
Our work on the structure and mechanism of each of these transporters has historically used techniques of membrane protein biochemistry, multiple types of spectroscopy, electrophysiology, and molecular biology. As more atomic level structures of transport proteins have become available, we have moved primarily to using molecular dynamics simulations of these transporters as a tool to elucidate dynamic mechanistic details that are defined by and constrained by the protein structures, and which cannot be captured by static protein structures.