LPA3receptors have orthosteric and allosteric binding sites evidenced under docking studies

Abstract

AbstractComparative studies using LPA and the synthetic ligand, oleoyl-methoxy glycerophosphothionate, OMPT, in cells expressing the LPA3receptor revealed differences in these agonists’ action. We observed that the latter agonist exhibits two very different potency values, one in the order of 1-10 nm and the other with 30-100-fold less potency and biased pharmacodynamic behavior. The possibility that more than one site might exist for this ligand in the LPA3receptor was considered. We performed comparative LPA and OMPT docking studies to obtain structural tridimensional details to achieve binding analysis exploring the whole protein. Our study includes blind docking using the unrefined and refined proteins subjected to hot spot predictions, which allowed us to detect that the LPA binding site is preferentially located in the cytoplasmic (orthosteric site) region. In contrast, OMPT displayed an affinity for an additional binding site (allosteric) located in transmembrane and extracellular regions.Docking studies also focused on the alpha carbons from Trp102 and Tyr293, founded as the centers for the hot spot predictions. Docking targeted to Trp102 favored binding both ligands in the transmembrane and extracellular regions. In contrast, docking targeted to Tyr293 also shared interaction sites for both ligands but in the cytoplasmic region. These data suggest that OMPT might exhibit a biotypic behavior, promoting different structural rearrangements, which could explain the observed biased behavior.One-sentence summary:Orthosteric and allosteric agonist binding sites in LPA3receptors