Abstract
CETP transfers cholesteryl esters (CEs) and triglycerides (TGs) between different lipoproteins and came in limelight as a drug-target against CVD. In the search for detailed mechanism of lipid transfer through CETP, enormous effort is devoted employing crystallographic, cryo-EM, and Molecular Dynamics (MD) studies. However, these studies primarily focused on CE-bound CETP structure and CE transfer mechanism. With the reported correlation that CETP looses significant CE transfer activity upon inhibiting TG transfer, it is of tremendous importance to understand the structure and dynamics of TG-bound CETP. Our results from large-scale all-atom and coarse-grained MD simulations show that CETP can accommodate two TG molecules in parallel N-N orientation with TG oleate chains majorly attaining the tuning-fork conformation. In TG-bound form, CETP not only maintained its secondary structures but also exhibited similar bending-twisting motions as reported for CE-CETP crystal structure. Obtained structural information are further validated by correlating to available functional data of 2–8 fold slower transfer rate of TG through CETP, where we show that TGs make 20% additional contacts with CETP compared to CEs. Identified CETP residues facilitating TG binding also match very well with reported mutagenesis data. The study could accelerate the drug-designing processes to combat CETP functionality and CVD.
Highlights
Cardiovascular disease (CVD) is one of the major causes of deaths in the world
It is seen that the hetero exchange of neutral lipids by cholesteryl ester transfer protein (CETP) between atheroprotective high-density lipoprotein (HDL) and atherogenic low-density lipoprotein (LDL) or VLDL has an outcome of cholesteryl esters (CEs)-depletion and TG-enrichment in HDL, which in turn catabolize HDL
Recent mutational studies have shown that CETP is an active TG transporter, since the protein looses significant CE transfer activity upon the inhibition of TG transfer by active mutations in the hydrophobic tunnel[19]
Summary
Cardiovascular disease (CVD) is one of the major causes of deaths in the world. Epidemiological analyses have identified multiple risk factors responsible for CVD. Clinical studies on genetically modified mice with deficient HDL metabolic proteins conveyed compelling evidence that HDL is an important regulator of atherosclerosis in dyslipidemic conditions[5] These findings have raised tremendous interest in utilizing HDL as a therapeutic target for the prevention of CVD. New inhibitors like anacetrapib[10] and BMS-79531111 are currently in active clinical trials with marginal side effects in CVD patients In spite of these developments, very little is known about the lipid transfer mechanism of CETP between HDL and LDLs13–18. The crystal structure shows a hydrophobic tunnel of length 60 Å running through the central core of CETP and occupied by two cholesteryl esters (CEs) and two plug-in phospholipids (PLs) Both this and available inhibitor bound CETP crystal structures[20] are seen to be in CE-bound conformation. We believe that this study would have important implications in CVD therapeutics targeting CETP functionality
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