Molecular modeling of lanthionine synthetase component C-like protein 2: a potential target for the discovery of novel type 2 diabetes prophylactics and therapeutics.

Abstract

The rates of type 2 diabetes (T2D) are rising to epidemic proportions in the US and worldwide. While current T2D medications are efficacious, significant side effects have limited their use and availability. Our laboratory has discovered that abscisic acid (ABA) exerts anti-diabetic effects, in part, by activating peroxisome proliferator-activated receptor γ (PPAR γ). However, since ABA does not bind to the ligand-binding domain (LBD) of PPAR γ, the mechanism of activation of PPAR γ by ABA remains unknown. Lanthionine synthetase component C-like protein 2 (LANCL2) was predicted to be a novel target for the binding and signaling of ABA in human granulocytes and rat insulinoma cells. The goal of this study was to determine whether LANCL2 is a molecular target of ABA and other PPAR γ agonists. To this end we performed homology modeling to construct a three-dimensional structure of LANCL2 using the crystal structure of LANCL1 as a template. Our molecular docking studies predicted that ABA and other PPAR γ agonists (e.g., rosiglitazone and pioglitazone) share a binding site on the surface of LANCL2. The identification of a binding site for PPAR γ agonists will facilitate the high-throughput virtual screening of large compound libraries and may shed new light on alternative mechanisms of PPAR γ activation.