Mechanisms
CETP can carry triglycerides too, not just cholesteryl esters, and simulations show why the slower TG transfer happens (Sci Rep 2017)
Original title: How cholesteryl ester transfer protein can also be a potential triglyceride transporter
Structural studies of CETP, a cardiovascular drug target that transfers cholesteryl esters (CEs) and triglycerides (TGs) between lipoproteins, have focused almost entirely on the CE-bound structure and CE transfer mechanism, even though CETP is known to lose significant CE transfer activity when TG transfer is blocked. This study used large-scale all-atom and coarse-grained molecular dynamics simulations to characterise the structure and dynamics of TG-bound CETP. CETP accommodated two TG molecules in a parallel N-N orientation, with the TG oleate chains mostly adopting a tuning-fork conformation, while maintaining its secondary structure and the same bending-twisting motions previously reported for the CE-bound crystal structure. The simulations explained the known 2 to 8-fold slower transfer rate of TG versus CE through CETP: TGs made 20% more contacts with the protein than CEs, and the CETP residues identified as facilitating TG binding matched existing mutagenesis data well. A purely computational structural study intended to inform CETP-targeted drug design.
Original 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.
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.