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First crystal structure of CETP reveals a 60-angstrom tunnel holding four lipid molecules (Nat Struct Mol Biol 2007)
Original title: Crystal structure of cholesteryl ester transfer protein reveals a long tunnel and four bound lipid molecules
Researchers solved the crystal structure of cholesteryl ester transfer protein (CETP) at 2.2-angstrom resolution, the first structural view of the protein that shuttles cholesteryl esters from atheroprotective HDL to atherogenic lower-density lipoproteins. The structure revealed a 60-angstrom-long tunnel filled with two hydrophobic cholesteryl esters and capped at each end by an amphiphilic phosphatidylcholine molecule. Both tunnel openings are large enough to admit lipid, aided by a flexible helix and possibly a mobile flap, and the concave surface of CETP curves to match the radius of HDL particles, suggesting conformational changes may accommodate larger lipoprotein particles. Point mutations that block the middle of the tunnel abolished lipid-transfer activity, indicating that neutral lipids pass through this single continuous tunnel. The authors conclude this structure clarifies how CETP moves lipids between lipoproteins and provides a template for structure-based design of CETP inhibitors.
Original abstract
Cholesteryl ester transfer protein (CETP) shuttles various lipids between lipoproteins, resulting in the net transfer of cholesteryl esters from atheroprotective, high-density lipoproteins (HDL) to atherogenic, lower-density species. Inhibition of CETP raises HDL cholesterol and may potentially be used to treat cardiovascular disease. Here we describe the structure of CETP at 2.2-A resolution, revealing a 60-A-long tunnel filled with two hydrophobic cholesteryl esters and plugged by an amphiphilic phosphatidylcholine at each end. The two tunnel openings are large enough to allow lipid access, which is aided by a flexible helix and possibly also by a mobile flap. The curvature of the concave surface of CETP matches the radius of curvature of HDL particles, and potential conformational changes may occur to accommodate larger lipoprotein particles. Point mutations blocking the middle of the tunnel abolish lipid-transfer activities, suggesting that neutral lipids pass through this continuous tunnel.
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.