Crystal structure of the human oxytocin receptor

Waltenspuehl, Yann; Schoeppe, Jendrik; Ehrenmann, Janosch; Kummer, Lutz; Plueckthun, A.

doi:10.1101/2020.02.21.958090

Cited by 14 publications

(32 citation statements)

References 67 publications

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“…Divalent cations such as Mg 2+ were shown to act as positive allosteric modulators of the human oxytocin receptor (OTR). Recent crystal structure of OTR (PDB: 6TPK) 39 indicated that the two residues E42 and D100 are close enough to establish a divalent coordination with Mg 2+ , although the density of a metal ion is missing in the present crystal structure due to the low resolution. Mutagenesis experiments also echoed this hypothesis: one of the single point mutants E42A and D100A, or the double mutant demonstrated a pronounced influence of Mg 2+ on the binding of different agonists to OTR.…”

Section: Orthosteric Metal Ions In Gpcrsmentioning

confidence: 72%

“…Mutagenesis experiments also echoed this hypothesis: one of the single point mutants E42A and D100A, or the double mutant demonstrated a pronounced influence of Mg 2+ on the binding of different agonists to OTR. Moreover, the affinity of agonist oxytocin increased 30‐fold against wild type OTR in the presence of 3 mM Mg 2+ , compared with to the absence of Mg 2+ 39 . Those findings imply that Mg 2+ coordinates with both OTR and the agonist molecule.…”

Section: Orthosteric Metal Ions In Gpcrsmentioning

confidence: 78%

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The role of metal ions in G protein‐coupled receptor signalling and drug discovery

Zou

Chan

et al. 2021

WIREs Comput Mol Sci

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Metal ions, such as Na+, Mg2+, Ca2+, and Zn2+, are highly abundant in biological systems. For many G protein‐coupled receptors (GPCRs), metal ions, especially Na+, have been found to stabilize the receptors' inactivate state preventing receptor activation. Besides this role, recent studies indicated that metal ions can modulate ligand–GPCR interactions allosterically. These findings on ion‐mediated GPCR signaling open new vistas for understanding the functioning of GPCRs and further could help in designing potent therapeutic compounds targeting GPCRs. Here we report on recent findings about role of orthosteric and allosteric metal ions in GPCR signaling and drug discovery. This article is categorized under: Structure and Mechanism > Molecular Structures Molecular and Statistical Mechanics > Molecular Mechanics Molecular and Statistical Mechanics > Molecular Interactions

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Section: Orthosteric Metal Ions In Gpcrsmentioning

confidence: 72%

Section: Orthosteric Metal Ions In Gpcrsmentioning

confidence: 78%

The role of metal ions in G protein‐coupled receptor signalling and drug discovery

Zou

Chan

et al. 2021

WIREs Comput Mol Sci

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“…However, limited evidence exists regarding the structural and/or functional consequences of SNPs in the Oxtr gene. To this end, it seems surprising that only very recently, the crystal structure of the human OXTR has been solved, although in an inactive form as complex with retosiban, a non-peptide antagonist [175].…”

Section: Translational Perspectivesmentioning

confidence: 99%

Brain oxytocin: how puzzle stones from animal studies translate into psychiatry

2020

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The neuropeptide oxytocin has attracted great attention of the general public, basic neuroscience researchers, psychologists, and psychiatrists due to its profound pro-social, anxiolytic, and "anti-stress" behavioral and physiological effects, and its potential application for treatment of mental diseases associated with altered socio-emotional competence. During the last decade, substantial progress has been achieved in understanding the complex neurobiology of the oxytocin system, including oxytocinergic pathways, local release patterns, and oxytocin receptor distribution in the brain, as well as intraneuronal oxytocin receptor signaling. However, the picture of oxytocin actions remains far from being complete, and the central question remains: "How does a single neuropeptide exert such pleotropic actions?" Although this phenomenon, typical for many of about 100 identified neuropeptides, may emerge from the anatomical divergence of oxytocin neurons, their multiple central projections, distinct oxytocin-sensitive cell types in different brain regions, and multiple intraneuronal signaling pathways determining the specific cellular response, further basic studies are required. In conjunction, numerous reports on positive effects of intranasal application of oxytocin on human brain networks controlling socio-emotional behavior in health and disease require harmonic tandems of basic researchers and clinicians. During the COVID-19 crisis in 2020, oxytocin research seems central as question of social isolation-induced inactivation of the oxytocin system, and buffering effects of either activation of the endogenous system or intranasal application of synthetic oxytocin need to be thoroughly investigated.

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“…Very recently, Waltenspühl et al were able to report the crystal structure of the human OTR, with and without interaction of an OTR-selective antagonist (19). However, there is still much to learn about the OTR since the identification of those residues important for ligand binding have yet to be fully identified.…”

Section: Oxytocin and Its Pathwaymentioning

confidence: 99%

Oxytocin in the Male Reproductive Tract; The Therapeutic Potential of Oxytocin-Agonists and-Antagonists

Stadler

Whittaker²,

Exintaris³

et al. 2020

Front. Endocrinol.

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In this review, the role of oxytocin and oxytocin-like agents (acting via the oxytocin receptor and belonging to the oxytocin-family) in the male reproductive tract is considered. Previous research (dating back over 60 years) is revised and connected with recently found aspects of the role oxytocin plays in male reproductive health. The local expression of oxytocin and its receptor in the male reproductive tract of different species is summarized. Colocalization and possible crosstalk to other agents and receptors and their resulting effects are discussed. The role of the newly reported oxytocin focused signaling pathways in the male reproductive tract, other than mediating contractility, is critically examined. The structure and effect of the most promising oxytocin-agonists and-antagonists are reviewed for their potential in treating male disorders with origins in the male reproductive tract such as prostate diseases and ejaculatory disorders.

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Crystal structure of the human oxytocin receptor

Cited by 14 publications

References 67 publications

The role of metal ions in G protein‐coupled receptor signalling and drug discovery

The role of metal ions in G protein‐coupled receptor signalling and drug discovery

Brain oxytocin: how puzzle stones from animal studies translate into psychiatry

Oxytocin in the Male Reproductive Tract; The Therapeutic Potential of Oxytocin-Agonists and-Antagonists

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