In Silico Description of the Direct Inhibition Mechanism of Endothelial Lipase by ANGPTL3

TL;DR

This study uses computer modeling to understand how ANGPTL3 inhibits endothelial lipase, which could help in developing new therapies for lipid-related diseases.

Contribution

The study identifies specific residues in ANGPTL3 that may form a molecular recognition site for endothelial lipase.

Findings

Three glutamates in ANGPTL3 (Glu154, Glu157, Glu160) recognize a positively charged patch on endothelial lipase.

Molecular dynamics simulations and docking revealed the interaction mechanism between ANGPTL3 and EL.

The findings provide a foundation for designing novel ANGPTL3 inhibitors.

Abstract

Angiopoietin-like protein 3 (ANGPTL3) is a plasmatic protein that plays a crucial role in lipoprotein metabolism by inhibiting the lipoprotein lipase (LPL) and the endothelial lipase (EL) responsible for the hydrolysis of phospholipids on high-density lipoprotein (HDL). Interest in developing new pharmacological therapies aimed at inhibiting ANGPTL3 has been growing due to the hypolipidemic and antiatherogenic profile observed in its absence. The goal of this study was the in silico characterization of the interaction between ANGPTL3 and EL. Because of the lack of any structural information on both the trimeric coiled-coil N-terminal domain of ANGPTL3 and the EL homodimer as well as data regarding their interactions, the first step was to obtain the three-dimensional model of these two proteins. The models were then refined via molecular dynamics (MD) simulations and used to investigate the interaction mechanism. The analysis of interactions in different docking poses and their refinement via MD allowed the identification of three specific glutamates of ANGPTL3 that recognize a positively charged patch on the surface of EL. These ANGPTL3 key residues, i.e., Glu154, Glu157, and Glu160, could form a putative molecular recognition site for EL. This study paves the way for future investigations aimed at confirming the recognition site and at designing novel inhibitors of ANGPTL3.

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