Cardiovascular diseases (CVDs) are the leading cause of death worldwide. Human cholesteryl esters (CEs) are naturally transferred from atheroprotective high-density lipoproteins (HDLs) to atherogenic low-density lipoproteins (LDLs) and very low-density lipoproteins (VLDLs) by cholesteryl ester transfer protein (CETP), resulting in a higher probability of CVDs. Finding out the mechanism of CETP in CE transport is an important basis for designing new CETP inhibitors for treating CVDs. This review is focused on the recent studies of CETP structure and interactions with lipoproteins. Transmission electron microscopy (TEM) studies showed that CETP not only can bind to HDL, LDL and VLDL into binary complexes, respectively, but also connects HDL and LDL or VLDL into a ternary complex via penetrating into the HDL core with its N-terminal domain and the LDL or VLDL surface with its C-terminal domain. Molecular dynamics simulations suggested that the penetrated distal ends are highly flexible under physiological conditions and when CETP contacts lipid droplets. This flexibility allows for large-scale conformational changes, and can even open pores in the distal ends. These pores and the original hydrophobic cavities within the CETP crystal structure are generally stable in physiological solution, and can even connect together into a continuous tunnel for CE transfer. Based on above results, scientists introduced and discussed the "tunnel" model for CETP-mediated lipid transfer in detail, and further suggested new interfaces of CETP for being targeted by a new generation CETP inhibitors to treat CVDs.

Contents
1 Introduction
2 Structure of CETP and lipoproteins by electron microscopy
2.1 Structure of the CETP·HDL complex by electron microscopy
2.2 3D reconstruction of CETP·HDL complex
2.3 Structure of the CETP·LDL and CETP·VLDL complexes by electron microscopy
2.4 Labeling of binding sites
2.5 Structure of the HDL·CETP·LDL and HDL·CETP·VLDL complexes by electron microscopy
2.6 Verification of CETP lipid transfer activity
3 CETP structural features by molecular dynamics simulations
3.1 Structural flexibility
3.2 Internal cavities and surface pores
3.3 Surface hydrophobicity
4 Tunnel mechanism for CETP-mediated lipid transfer
4.1 "Tunnel" model for CETP-mediated lipid transfer
4.2 CETP-lipoprotein binding
4.3 Formation of transfer tunnel
4.4 Neutral lipid transfer
5 Conclusions and outlook