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Updated: Oct 1, 2025

Transmembrane Domain Oligomerization Propensity determined by ToxR Assay
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The oxytocin signaling complex reveals a molecular switch for cation dependence

Justin G Meyerowitz1,2,3, Michael J Robertson1,3, Ximena Barros-Álvarez1,3

  • 1Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA.

Nature Structural & Molecular Biology
|March 4, 2022
PubMed

Insights

We solved the structure of the active oxytocin receptor (OTR) bound to oxytocin (OT), revealing a novel Mg2+-dependent activation mechanism. This discovery offers insights into receptor function and aids drug development for conditions like autism and postpartum hemorrhage.

Area of Science:

  • Structural Biology
  • Molecular Pharmacology
  • Neuroendocrinology

Background:

  • Oxytocin (OT) and vasopressin (AVP) are vital peptide hormones regulating physiological and social behaviors.
  • The oxytocin receptor (OTR), a therapeutic target, mediates OT's actions but its activation mechanism, especially magnesium dependence, is unclear.

Purpose of the Study:

  • To elucidate the molecular mechanisms of human oxytocin receptor (OTR) activation by oxytocin (OT).
  • To understand the role of magnesium (Mg2+) in OTR function.
  • To investigate cation dependence across vasopressin family receptors.

Main Methods:

  • Determined the wild-type active-state structure of human OTR bound to OT and miniGq/i using cryo-electron microscopy (cryo-EM).
  • Performed functional assays to validate structural findings and explore agonism mechanisms.
  • Analyzed cation-coordinating residues to understand receptor cation dependence.

Main Results:

  • Revealed a unique OTR activation mechanism involving a Mg2+ coordination complex between OT and OTR.
  • Identified disruption of transmembrane helix 7 (TM7) by OT as a key activation step.
  • Demonstrated how specific residues dictate cation dependence in vasopressin family receptors.

Conclusions:

  • The Mg2+-dependent activation of OTR by OT involves Mg2+ complexation and TM7 disruption.
  • These findings provide a structural basis for OTR function and drug discovery.
  • The study clarifies molecular determinants of cation dependence in related receptors.

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