G protein-coupled receptors (GPCRs) are important signaling molecules in eukaryotes. Strategically located at the cellular periphery, these integral membrane proteins transmit extracellular information into the cell. Although a third of all drugs target GPCRs, their mechanisms of signal transduction remain poorly understood. To enhance our understanding of GPCR function, we must define the mechanisms by which extracellular agonist binding induces receptor reorganization and subsequent activation of cytosolic signaling proteins. Concurrently, we must characterize the ways in which this process is influenced by different components of the richly heterogeneous cell membrane.
Many types of cancer are driven by oncogenic mutations that trap small GTPases in active states. I am studying one such protein, ras, whose aberrant signaling is implicated in a third of all cancers, especially those of the lung, colon, and pancreas. I am using enhanced sampling methods to define the clustering of ras in membranes, and the preferential interactions of ras with different types of membrane lipids.
The functional dynamics of membrane proteins are influenced by lipid composition, which controls membrane bulk properties such as thickness, fluidity, and surface potential, and provisions lipid species that can engage in specific and functionally relevant lipid-protein interactions. Nevertheless, previous theoretical studies of GPCRs have mainly considered the cell membrane as a passive solvent. I seek to understand how the native environment of these receptors influences their structure and dynamics, and hypothesize that specific interactions between GPCRs and other membrane components regulate receptor activity. My long-term objectives are to elucidate protein-membrane interactions that affect GPCR signaling and to understand how their interplay allows GPCRs to integrate complex information for the cell.
Using computer simulations, I have undertaken a research program to define the ways in which the receptor's environment impacts its functional dynamics. I have identified a conserved regulatory mechanism in which membrane components stabilize the receptor's active state prior to G protein binding. My proposed research will lead to new understandings of GPCR function in native environments, a crucial step in defining how these druggable receptors work.
The resulting understanding of the structure, clustering, and membrane partitioning of ras will provide atomistic models of new, potentially druggable surfaces on this key driver of cancer, whose generally smooth surface (absent substantial hydrophobic pockets to which conventional drugs may bind) has to this point resisted pharmacological efforts.