Crystal structure of the human oxytocin receptor

The peptide hormone oxytocin modulates socioemotional behaviour and sexual reproduction via the centrally expressed oxytocin receptor (OTR) across several species. Here, we report the crystal structure of human OTR in complex with retosiban, a non-peptide antagonist developed as an oral drug for the prevention of preterm labour. Our structure reveals insights into the detailed interactions between the G-protein coupled receptor (GPCR) and an OTR-selective antagonist. The observation of an extrahelical cholesterol molecule, binding in an unexpected location between helix IV and V, provides a structural rationale for its allosteric effect and critical influence on OTR function. Furthermore, our structure in combination with experimental data allows the identification of a conserved neurohypophyseal receptor-specific coordination site for Mg2+ that acts as potent positive allosteric modulator for agonist binding. Together these results further our molecular understanding of the oxytocin/vasopressin receptor family and will facilitate structure-guided development of new therapeutics.