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Nat Chem Biol. 2012 Feb 19;8(4):342-9. doi: 10.1038/nchembio.796.

Structural basis of transfer between lipoproteins by cholesteryl ester transfer protein.

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  • 1Molecular Foundry, Lawrence Berkeley National Laboratory, Berkeley, California, USA.

Abstract

Human cholesteryl ester transfer protein (CETP) mediates the net transfer of cholesteryl ester mass from atheroprotective high-density lipoproteins to atherogenic low-density lipoproteins by an unknown mechanism. Delineating this mechanism would be an important step toward the rational design of new CETP inhibitors for treating cardiovascular diseases. Using EM, single-particle image processing and molecular dynamics simulation, we discovered that CETP bridges a ternary complex with its N-terminal β-barrel domain penetrating into high-density lipoproteins and its C-terminal domain interacting with low-density lipoprotein or very-low-density lipoprotein. In our mechanistic model, the CETP lipoprotein-interacting regions, which are highly mobile, form pores that connect to a hydrophobic central cavity, thereby forming a tunnel for transfer of neutral lipids from donor to acceptor lipoproteins. These new insights into CETP transfer provide a molecular basis for analyzing mechanisms for CETP inhibition.

PMID:
22344176
[PubMed - indexed for MEDLINE]
PMCID:
PMC3792710
Free PMC Article

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