STRUCTURAL STUDIES ON LIGAND AND LIPID MODULATION OF THE CAPSAICIN RECEPTOR, TRPV1
When integral membrane proteins are visualized in detergents or other artificial systems, an important layer of information is lost regarding lipid interactions and their effects on protein structure. This is especially relevant to proteins for which lipids play both structural and regulatory roles. Here, we demonstrate the power of combining electron cryo-microscopy with lipid nanodisc technology to ascertain the structure of an integral membrane protein - the TRPV1 ion channel - in a native bilayer environment. Using this approach, we could ascertain the locations of annular and regulatory lipids, enabling us to show that specific phospholipid interactions enhance binding of a spider toxin to TRPV1 through formation of a tripartite complex. Furthermore, phosphatidylinositol lipids occupy the binding site for capsaicin and other vanilloid ligands, suggesting a mechanism whereby chemical or thermal stimuli elicit channel activation by promoting release of bioactive lipids from a critical allosteric regulatory site.