| Autor: |
Montavoci L; Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Via Giuseppe Balzaretti 9, 20133 Milan, Italy., Ben Mariem O; Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Via Giuseppe Balzaretti 9, 20133 Milan, Italy., Saporiti S; Analytical Excellence and Program Management, Merck Serono S.p.A., Via Luigi Einaudi 11, Guidonia Montecelio, 00012 Rome, Italy., Laurenzi T; Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Via Giuseppe Balzaretti 9, 20133 Milan, Italy., Palazzolo L; Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Via Giuseppe Balzaretti 9, 20133 Milan, Italy., Ossoli AF; Centro E. Grossi Paoletti, Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Via Giuseppe Balzaretti 9, 20133 Milan, Italy., Guerrini U; Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Via Giuseppe Balzaretti 9, 20133 Milan, Italy., Calabresi L; Centro E. Grossi Paoletti, Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Via Giuseppe Balzaretti 9, 20133 Milan, Italy., Eberini I; Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Via Giuseppe Balzaretti 9, 20133 Milan, Italy.; Data Science Research Center (DSRC), Università degli Studi di Milano, Via Giuseppe Balzaretti 9, 20133 Milan, Italy. |
| Abstrakt: |
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. |
