Biophysical Society Conference | Tahoe 2024

Molecular Biophysics of Membranes

Monday Speaker Abstracts


ENHANCED TOOLS AND STRATEGIES FOR EXPLORATION OF STRUCTURE, FUNCTION, AND INHIBITION AT PROTEIN-MEMBRANE INTERFACES. Brian Fuglestad 1 ; 1 Virginia Commonwealth University, Department of Chemistry, Richmond, VA, USA Peripheral membrane proteins (PMPs) are water-soluble proteins that reversibly bind to membranes to perform their function. Despite a central role in a variety of biological and disease related processes, study of their functional membrane-bound forms have been hampered by technical limitations. Additionally, interest in targeting membrane proteins, including PMPs, for therapeutic intervention has grown recently. However, discovery tools for this class of protein is limited. To better understand the active, membrane bound state of PMPs, a larger toolbox must be developed. Our recently developed membrane-mimicking reverse micelles (mmRMs) are a valuable addition to the methodologies available to study PMPs using NMR and other biophysical methods. We have applied mmRMs to a variety of problems including structural study of a lipid chaperone, fatty acid binding protein 4 (FABP4), which has unveiled the structure of the elusive membrane-bound form of the protein and revealed a mechanism for lipid uptake. Fragment-based drug discovery of PMPs using biophysical methods is proving to be a promising path, demonstrated by successful screening of PX domain of p47 phox with the goal of inhibiting of its membrane anchoring event. Conversely, proteins such as glutathione peroxidase 4 (GPx4), which are not amenable to inhibition through this strategy, present a greater challenge. Applying a fragment screening approach to the active, membrane-bound form of GPx4 housed in mmRMs has revealed small-molecule interactions within the protein-membrane interface, a challenging space for inhibitor development. Not only do these fragments represent starting points for inhibitor development, they also reveal fundamental properties about molecular interactions in the membrane-protein interface. The approaches presented here will enhance our understanding of PMPs in their functional, membrane bound state and provide avenues for building inhibitors for this challenging category of protein.


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