bi9b00301_si_003.mpg (10.17 MB)
Steering the Lipid Transfer To Unravel the Mechanism of Cholesteryl Ester Transfer Protein Inhibition
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posted on 2019-08-22, 19:15 authored by Sneha
M. Dixit, Mohd Ahsan, Sanjib SenapatiHuman
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.