Molecular modeling of the human serotonin 1A receptor: role of membrane cholesterol in ligand binding of the receptor

Serotonin1A 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 serotonin1Areceptor has not been solved yet. Earlier homology models of the serotonin1Areceptor 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 serotonin1Areceptor. Since the sequence similarity between the serotonin1Areceptor and β2-adrenergic receptor is considerably higher than the similarity between the serotonin1Areceptor and rhodopsin, our model is more reliable. Based on these templates, we generated models of the serotonin1Areceptor 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 serotonin1Areceptor. 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.