Department of Biochemistry, University of Zürich, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland.
Sci Adv. 2020 Jul 15;6(29):eabb5419. doi: 10.1126/sciadv.abb5419. eCollection 2020 Jul.
The peptide hormone oxytocin modulates socioemotional behavior 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 nonpeptidic antagonist developed as an oral drug for the prevention of preterm labor. 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 helices 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 Mg 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.
肽激素催产素通过中枢表达的催产素受体（OTR）在多种物种中调节社会情感行为和性生殖。在这里，我们报告了与人 OTR 复合物的晶体结构与 retosiban，一种非肽类拮抗剂开发作为一种口服药物，以防止早产。我们的结构揭示了详细的相互作用之间的 G 蛋白偶联受体（GPCR）和 OTR 选择性拮抗剂。观察到一个额外的螺旋胆固醇分子，结合在一个意想不到的位置之间的 IV 和 V 螺旋，提供了一个结构的理由，其变构效应和对 OTR 功能的关键影响。此外，我们的结构与实验数据相结合，可以确定一个保守的神经垂体受体特异性协调镁的作用是强大的，正变构调节剂激动剂结合。总之，这些结果进一步我们的分子理解的催产素/加压素受体家族，并将促进结构为导向的开发新的治疗方法。
