Steering the Lipid Transfer To Unravel the Mechanism of Cholesteryl Ester Transfer Protein Inhibition

Abstract

Human plasma cholesteryl ester transfer protein (CETP) mediates the transfer of neutral lipids from antiatherogenic high-density lipoproteins (HDLs) to proatherogenic low-density lipoproteins (LDLs). Recent cryo-electron microscopy studies have suggested that CETP penetrates its N- and C-terminal domains in HDL and LDL to form a ternary complex, which facilitates the lipid transfer between different lipoproteins. Inhibition of CETP lipid transfer activity has been shown to increase the plasma HDL-C levels and, therefore, became an effective strategy for combating cardiovascular diseases. Thus, understanding the molecular mechanism of inhibition of lipid transfer through CETP is of paramount importance. Recently reported inhibitors, torcetrapib and anacetrapib, exhibited low potency in addition to severe side effects, which essentially demanded a thorough knowledge of the inhibition mechanism. Here, we employ steered molecular dynamics simulations to understand how inhibitors interfere with the neutral lipid transfer mechanism of CETP. Our study revealed that inhibitors physically occlude the tunnel posing a high energy barrier for lipid transfer. In addition, inhibitors bring about the conformational changes in CETP that hamper CE passage and expose protein residues that disrupt the optimal hydrophobicity of the CE transfer path. The atomic level details presented here could accelerate the designing of safe and efficacious CETP inhibitors.

Bound Phospholipids Assist Cholesteryl Ester Transfer in the Cholesteryl Ester Transfer Protein

“…before its exit from the C-terminal tip with an energy of nearly −40 kcal mol –1 with the help of residues like PHE292, ALA319, PHE350, and LEU409. The observed trend was very similar to previous reports. , A clear evidence of differential energy contributions was observed when CE was transferring in the hydrophobic tunnel.…”

“…The observed trend was very similar to previous reports. 17,41 A clear evidence of differential energy contributions was observed when CE was transferring in the hydrophobic tunnel.…”

“…13−15 CETP has become a well-known and viable target in the fight against CVDs. 16,17 In order to raise HDL-C levels and limit CETP activity, extensive research is being carried out to prevent CVDs.…”

“…Also, recent research has demonstrated a striking decrease in HDL-C levels when the human CETP gene is expressed in mice, which leads to the development of atherosclerotic lesions . Several investigations using rabbit models have demonstrated that inhibiting CETP can lessen the likelihood of atherosclerosis. − CETP has become a well-known and viable target in the fight against CVDs. , In order to raise HDL-C levels and limit CETP activity, extensive research is being carried out to prevent CVDs.…”

Deciphering structural aspects of reverse cholesterol transport: mapping the knowns and unknowns

“…Once CETP binds to the HDL surface, CE molecules are pulled to the surface where the N-terminus of CETP interacts with HDL, forming a hydrophobic patch (Cilpa-Karhu et al, 2015). Hydrophobic interactions between CE fatty tails and CETP residues (Phe115 and Phe167) at the beginning of the tunnel and the 'peristaltic' movement of CETP drive lipid transfer through the tunnel (Lei et al, 2016;Dixit, Ahsan & Senapati, 2019). Deciphering structural aspects of RCT facilitates remodelling by modulating the size and composition of HDL.…”