Molecular modeling of the human serotonin1Areceptor: role of membrane cholesterol in ligand binding of the receptor

Abstract

Serotonin_1A receptors are important neurotransmitter receptors and belong to the superfamily of G-protein coupled receptors (GPCRs). Although it is an important drug target, the crystal structure of the serotonin_1Areceptor has not been solved yet. Earlier homology models of the serotonin_1Areceptor were generated using rhodopsin as a template. We have used two recent crystal structures of the human β₂-adrenergic receptor, one of which shows specific cholesterol binding site(s), as templates to model the human serotonin_1Areceptor. Since the sequence similarity between the serotonin_1Areceptor and β₂-adrenergic receptor is considerably higher than the similarity between the serotonin_1Areceptor and rhodopsin, our model is more reliable. Based on these templates, we generated models of the serotonin_1Areceptor in the absence and presence of cholesterol. The receptor model appears more compact in the presence of cholesterol. We validated the stability of ‘compactness’ using coarse-grain MD simulation. Importantly, all ligands exhibit higher binding energies when docked to the receptor in the presence of cholesterol, thereby implying that membrane cholesterol facilitates ligand binding to the serotonin_1Areceptor. To the best of our knowledge, this is one of the first reports in which lipid-specific receptor conformations have been modeled by homology modeling.