TRPV1 structures in nanodiscs reveal mechanisms of ligand and lipid action

Yuan Gao, Erhu Cao, David Julius () and Yifan Cheng ()
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Yuan Gao: University of California
Erhu Cao: University of California
David Julius: University of California
Yifan Cheng: University of California

Nature, 2016, vol. 534, issue 7607, 347-351

Abstract: Abstract 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 have both structural and regulatory roles. Here we demonstrate the power of combining electron cryo-microscopy with lipid nanodisc technology to ascertain the structure of the rat TRPV1 ion channel in a native bilayer environment. Using this approach, we determined the locations of annular and regulatory lipids and showed 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 the release of bioactive lipids from a critical allosteric regulatory site.

Date: 2016
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DOI: 10.1038/nature17964

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