Key findings
- A cryo-electron microscopy structure of the wild-type human receptor bound to the peptide and to miniGq/i shows activation running through a magnesium coordination complex formed between peptide and receptor together with disruption of transmembrane helix 7. [1]
- The crystal structure of the same receptor with the nonpeptidic antagonist retosiban resolved an extrahelical cholesterol molecule between helices IV and V and a conserved magnesium coordination site that acts as a positive allosteric modulator of agonist binding. [2]
- Copper and zinc each bound the peptide with a distinct far-UV circular dichroism signature, and both metal bound forms attenuated MAPK activation on receptor binding relative to the peptide alone, while the zinc bound linear form raised MAPK signalling. [3]
- A cell line stably expressing the A218T receptor variant showed higher receptor protein stability, a shifted calcium response and reduced MAPK pathway activation compared with the wild-type receptor line. [4]
Identity and structure
- Composition
- A nine-residue peptide hormone first described in 1954 [3]
- Disulfide
- The native sequence carries a labile disulfide bond between two cysteine residues, which analogue work replaces with a lactam to obtain a stable ring [5]
- Cation requirement
- The receptor is magnesium dependent, and the cation coordination site is conserved across neurohypophyseal receptors [1][2]
- Preparation route in cited work
- Fmoc solid phase synthesis with side chain deprotection, cleavage from the resin, oxidative folding, purification and analysis [6]
- Form as supplied
- Sterile lyophilized powder
Mechanism as studied
Activation of the receptor by the peptide is described structurally rather than inferred. The active-state complex shows the peptide and receptor together coordinating a magnesium ion and the peptide disrupting transmembrane helix 7, and functional assays in the same work separate full agonism by the native peptide from partial agonism by analogues. [1]
Cation dependence is a family level property traced to one residue. The same work reports that the identity of a single cation-coordinating residue across vasopressin family receptors decides whether a given receptor is cation dependent, and the antagonist-bound crystal structure independently places a conserved magnesium site acting as a positive allosteric modulator. [1][2]
Cholesterol is treated as a second allosteric input. The crystal structure resolved one extrahelical cholesterol between helices IV and V, and docking with molecular dynamics found further sites whose occupancy differs between agonist-bound and antagonist-bound states, with network analysis tracing paths from those sites to the orthosteric pocket. [2][7]
Research findings
Structural
- System
- Wild-type human oxytocin receptor bound to the native peptide and to a miniGq/i protein, solved by cryo-electron microscopy, with parallel signalling assays
- Measured
- The active-state receptor structure, the magnesium coordination geometry, the conformation of transmembrane helix 7, agonist response of the native peptide and of analogues, and the effect of the cation-coordinating residue identity across vasopressin family receptors
- Reported
- The structure shows a magnesium coordination complex formed between peptide and receptor and disruption of transmembrane helix 7 by the peptide. Functional assays tie that disruption to full agonism by the native peptide and to partial agonism by analogues, and a single cation-coordinating residue determines whether a family receptor is cation dependent. [1]
Structural
- System
- Human oxytocin receptor in complex with the nonpeptidic selective antagonist retosiban, so the resolved ligand is an antagonist rather than the catalog peptide
- Measured
- Crystal structure of the receptor antagonist complex, the position of a bound cholesterol molecule and, with accompanying experimental data, a conserved cation coordination site
- Reported
- The structure details the interactions between the receptor and a selective antagonist, places an extrahelical cholesterol between helices IV and V as a structural rationale for its allosteric effect, and identifies a conserved magnesium coordination site that acts as a positive allosteric modulator of agonist binding. [2]
Structural
- System
- Computational models of the oxytocin receptor in its agonist-bound and antagonist-bound states, compared against an experimental cryo-electron microscopy density map
- Measured
- Cholesterol binding sites, their distributions and residence times by molecular docking and molecular dynamics, and allosteric network paths to the orthosteric pocket
- Reported
- Both methods converged on several cholesterol sites with differing occupancy between the two receptor states, one of which coincides with density in the experimental map. Network analysis highlights one extracellular leaflet site between TM4 and TM5 and two intracellular leaflet sites as paths that transmit allosteric signal to the orthosteric pocket. [7]
In vitro
- System
- The peptide and related analogues in solution with copper and zinc, then applied to receptor expressing cells
- Measured
- Far-UV circular dichroism of the metal bound forms, and MAPK pathway activation following receptor binding
- Reported
- Copper and zinc each bound the peptide and every analogue tested with a distinct signature. Both metal bound forms of the cyclic peptide attenuated MAPK activation relative to the peptide alone, while zinc bound forms of the linear peptide increased MAPK signalling. [3]
In vitro
- System
- Two monoclonal HEK293 lines stably expressing either the wild-type receptor or the A218T variant, with computational modelling of the variant alongside
- Measured
- Receptor protein stability, calcium dynamics, MAPK pathway activation, and whole-genome plus RNA sequencing of the peptide exposed cells
- Reported
- The variant line showed increased receptor protein stability, a shift in calcium dynamics and reduced MAPK activation. Sequencing found 7823 differentially regulated genes between the variant and wild-type lines, and the modelling gave a structural basis for the stability change. [4]
Ex vivo
- System
- Sagittal sections of postnatal day 0 wild-type and receptor knockout mice, probed with an iodinated ornithine vasotocin analogue rather than with labelled oxytocin itself
- Measured
- Receptor autoradiography signal across peripheral tissues, and radioligand selectivity by competition against unlabelled peptide in both genotypes
- Reported
- Specific binding appeared in the oronasal cavity, the eye, whisker pads, adrenal gland and anogenital region of wild-type tissue and was absent in knockout tissue. Signal in brown adipose tissue and liver was present in both genotypes and could not be competed away, and the authors classify it as nonspecific binding to high lipid content regions. [8]
Handling for in-vitro work
- Folding step in cited work
- Oxidative folding after cleavage from the solid support closes the disulfide bond, followed by purification and analysis [6]
- Buffer cation in cited work
- Magnesium is required for receptor activation and acts as a positive allosteric modulator of agonist binding in the cited structural work [1][2]
- Storage
- Lyophilized at -20 °C, dark and dry; reconstituted aliquots kept cold and used promptly
Open questions
- The antagonist-bound crystal structure and the agonist-bound cryo-electron microscopy structure describe different receptor states, and the cited work does not reconcile the cholesterol site occupancies between them experimentally.
- The cholesterol network analysis is computational, and the cited authors present its sites as targets for experimental testing rather than as measured allosteric couplings.
- Whether the copper and zinc bound forms occur at meaningful proportions in a given preparation is not addressed by the circular dichroism work.
- The neonatal autoradiography used a labelled vasotocin analogue, so the mapped sites report receptor distribution rather than distribution of this peptide.
An extensive clinical literature on this hormone exists, covering obstetric and behavioural research with finished formulations. It is out of scope for a research material profile and none of it is summarized here.
Lot records
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No published lot is available for this exact compound name.
Read a certificate of analysis ↗References
- Meyerowitz JG, Robertson MJ, Barros-Álvarez X, et al. The oxytocin signaling complex reveals a molecular switch for cation dependence. Nature structural & molecular biology. 2022.
- Waltenspühl Y, Schöppe J, Ehrenmann J, et al. Crystal structure of the human oxytocin receptor. Science advances. 2020.
- O'Sullivan JJ, Uyeda KS, Stevenson MJ, et al. Investigation of metal modulation of oxytocin structure receptor-mediated signaling. RSC chemical biology. 2023.
- Meyer M, Jurek B, Alfonso-Prieto M, et al. Structure-function relationships of the disease-linked A218T oxytocin receptor variant. Molecular psychiatry. 2022.
- Szabó LZ, Tanguturi P, Goodman HJ, et al. Structure-Based Design of Glycosylated Oxytocin Analogues with Improved Selectivity and Antinociceptive Activity. ACS medicinal chemistry letters. 2023.
- Kremsmayr T, Muttenthaler M Fmoc Solid Phase Peptide Synthesis of Oxytocin and Analogues. Methods in molecular biology (Clifton, N.J.). 2022.
- Marlow B, Vogel A, Kuenze G, et al. Cholesterol allosteric modulation of the oxytocin receptor. Biophysical journal. 2025.
- Greenwood MA, Hammock EA Oxytocin receptor binding sites in the periphery of the neonatal mouse. PloS one. 2017.
Publication records fetched from PubMed on 2026-09-20. Profile text reviewed 2026-09-20.