Dataset Information

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

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.

SUBMITTER: Montavoci L

PROVIDER: S-EPMC10971391 | biostudies-literature | 2024 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Montavoci Linda L Ben Mariem Omar O Saporiti Simona S Laurenzi Tommaso T Palazzolo Luca L Ossoli Alice Federica AF Guerrini Uliano U Calabresi Laura L Eberini Ivano I

International journal of molecular sciences 20240321 6

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 characteriza ...[more]

PMID: 38542527

Similar Datasets

Project description:The molecular mechanism of transport mediated by LAT1, a sodium-independent antiporter of large neutral amino acids, was investigated through in silico procedures, specifically making reference to two transported substrates, tyrosine (Tyr) and leucine methyl ester (LME), and to 3,5-diiodo-L-tyrosine (DIT), a well-known LAT1 inhibitor. Two models of the transporter were built by comparative modeling, with LAT1 either in an outward-facing (OF) or in an inward-facing (IF) conformation, based, respectively, on the crystal structure of AdiC and of GadC. As frequently classic Molecular Dynamics (MD) fails to monitor large-scale conformational transitions within a reasonable simulated time, the OF structure was equilibrated for 150 ns then processed through targeted MD (tMD). During this procedure, an elastic force pulled the OF structure to the IF structure and induced, at the same time, substrates/inhibitor to move through the transport channel. This elastic force was modulated by a spring constant (k) value; by decreasing its value from 100 to 70, it was possible to comparatively account for the propensity for transport of the three tested molecules. In line with our expectations, during the tMD simulations, Tyr and LME behaved as substrates, moving down the transport channel, or most of it, for all k values. On the contrary, DIT behaved as an inhibitor, being (almost) transported across the channel only at the highest k value (100). During their transit through the channel, Tyr and LME interacted with specific amino acids (first with Phe252 then with Thr345, Arg348, Tyr259, and Phe262); this suggests that a primary as well as a putative secondary gate may contribute to the transport of substrates. Quite on the opposite, DIT appeared to establish only transient interactions with side chains lining the external part of the transport channel. Our tMD simulations could thus efficiently discriminate between two transported substrates and one inhibitor, and therefore can be proposed as a benchmark for developing novel LAT1 inhibitors of pharmacological interest.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets