Molecular modeling of the oxytocin receptor/bioligand interactions

Oxytocin is a nonapeptide hormone (CYIQNCPLG-NH2, OT), controlling labor an d lactation in mammalian females, via interactions with specific cellular m embrane receptors (OTRs). The native hormone is cyclized via a 1-6 disulfid e and its receptor belongs to the GTP-binding (G) protein-coupled receptor (GPCR) family, also known as heptahelical transmembrane (7TM) or serpentine receptors. Using a technique combining multiple sequence alignments with a vailable experimental constraints, a reliable OTR model was built. Subseque ntly, the OTR complexes with a selective agonist [Thr(4),Gly(7)]OT, a selec tive cyclohexapeptide antagonist L-366,948 and oxytocin itself were modeled and relaxed using a constrained simulated annealing (CSA) protocol. All th ree ligands seem to prefer similar modes of binding to the receptor, manife sted by repeating receptor residues which directly interact with the ligand s. Those involved in the three complexes are putative helices: TM3: R113, K 116, Q119, M123; TM4: Q171, and TM5: I201 and T205. Most of them are the eq uivalent residues/positions to those found in our earlier studies, regardin g related vasopressin V2 receptor/bioligand interactions.