Peripheral membrane and lipid transfer proteins

The membranes of a cell are hotspots of biological activity. In turn, many diseases proceed through action within or involving cellular membranes. Peripheral membrane proteins interact with membranes, often reversibly, to perform a variety of functions. Lipid transport proteins shuttle lipid between membranes. Technical and methodological limitations have hindered a full understanding of these classes of proteins in their functional, membrane-adhered states. We are interested in structural biology, biophysical and functional study of these proteins. This information is used to inform rational drug design efforts to block the disease causing action of these proteins. The ultimate goal of the Fuglestad Lab is to enhance our understanding of peripheral membrane and lipid transport proteins, inhibit them for chemical biology investigations, and to develop drugs to treat disease such as cancer and cardiovascular disorders.

New tools to study protein interactions with membranes and lipids

Understanding the interactions between peripheral membrane proteins and lipids is of paramount importance in strategizing therapeutics. We use a number of models of biological membranes to probe the interactions between proteins and cellular membranes. Of particular expertise in the Fuglestad Lab is leveraging reverse micelles as membrane mimics, which has several advantages over other more commonly used membrane models. Recent developments have moved reverse micelles closer to the chemistry found in cellular membranes, allowing more physiologically relevant studies of protein interactions with membranes. We employ a multitude of techniques to study protein/membrane interactions including protein nuclear magnetic resonance (NMR) spectroscopy, MD simulations, fluorescence, and small-angle scattering, among others.

Fragment screening and inhibitor design

Rational design of inhibitors uses information about the structure and function of the protein target of interest. Fragment based inhibitor design is a powerful approach that is useful for traditionally difficult protein targets. This involves screening proteins for small inhibitor building blocks rather than larger drug-like molecules. Peripheral membrane proteins are particularly challenging proteins for inhibitor and drug development. We employ established fragment screening methods and develop new technologies to enable fragment-based drug design of membrane embedded proteins. The information gained form these screens is used in highly collaborative efforts in inhibitor development for the ultimate goal of obtaining chemical biology tools and drug leads.