Crystal structure of the human oxytocin receptor

AbstractThe 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.

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Crystal structure of the human oxytocin receptor

Science Advances ◽

10.1126/sciadv.abb5419 ◽

2020 ◽

Vol 6 (29) ◽

pp. eabb5419 ◽

Cited By ~ 2

Author(s):

Yann Waltenspühl ◽

Jendrik Schöppe ◽

Janosch Ehrenmann ◽

Lutz Kummer ◽

Andreas Plückthun

Keyword(s):

Crystal Structure ◽

Preterm Labor ◽

Peptide Hormone ◽

Oxytocin Receptor ◽

Oral Drug ◽

Allosteric Modulator ◽

Agonist Binding ◽

Positive Allosteric Modulator ◽

G Protein Coupled ◽

Receptor Family

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 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.

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Oxytocin as a Metabolic Modulator

10.5772/intechopen.97630 ◽

2021 ◽

Author(s):

Neeru Bhatt

Keyword(s):

Diabetes Mellitus ◽

Enzyme Activity ◽

Developmental Trajectories ◽

Sugar Metabolism ◽

Peptide Hormone ◽

Endocrine Disorders ◽

Metabolic Hormones ◽

Amino Acid Peptide ◽

G Protein Coupled ◽

Receptor Family

Oxytocin (9-amino acid peptide) hormone is a member of the G-protein coupled receptor family. It regulates a range of physiologic actions in mammals other than assisting parturition and lactation functions. Evidence indicates that oxytocin alters lipids, protein, and sugar metabolism through various ways including modulation of appetite and satiety, enzyme activity, cellular signals, secretion of metabolic hormones, and energy consumption. Alterations in these processes have the potential to shift developmental trajectories and influence disease processes. Oxytocin can be a potential avenue for the treatment of endocrine disorders such as obesity, diabetes mellitus, and associated disorders. The chapter will include a comprehensive study about oxytocin and its physiological and pathological functions, which makes it a potential target for drug therapy.

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Ca2+ allostery in PTH-receptor signaling

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1814670116 ◽

2019 ◽

Vol 116 (8) ◽

pp. 3294-3299 ◽

Cited By ~ 13

Author(s):

Alex D. White ◽

Fei Fang ◽

Frédéric G. Jean-Alphonse ◽

Lisa J. Clark ◽

Hyun-Jung An ◽

...

Keyword(s):

Kinetic Studies ◽

Receptor Activation ◽

Mass Accuracy ◽

Camp Signaling ◽

Allosteric Modulator ◽

Extracellular Loop ◽

Camp Production ◽

Positive Allosteric Modulator ◽

Early Endosomes ◽

G Protein Coupled

The parathyroid hormone (PTH) and its related peptide (PTHrP) activate PTH receptor (PTHR) signaling, but only the PTH sustains GS-mediated adenosine 3′,5′-cyclic monophosphate (cAMP) production after PTHR internalization into early endosomes. The mechanism of this unexpected behavior for a G-protein–coupled receptor is not fully understood. Here, we show that extracellular Ca2+ acts as a positive allosteric modulator of PTHR signaling that regulates sustained cAMP production. Equilibrium and kinetic studies of ligand-binding and receptor activation reveal that Ca2+ prolongs the residence time of ligands on the receptor, thus, increasing both the duration of the receptor activation and the cAMP signaling. We further find that Ca2+ allostery in the PTHR is strongly affected by the point mutation recently identified in the PTH (PTHR25C) as a new cause of hypocalcemia in humans. Using high-resolution and mass accuracy mass spectrometry approaches, we identified acidic clusters in the receptor’s first extracellular loop as key determinants for Ca2+ allosterism and endosomal cAMP signaling. These findings coupled to defective Ca2+ allostery and cAMP signaling in the PTHR by hypocalcemia-causing PTHR25C suggest that Ca2+ allostery in PTHR signaling may be involved in primary signaling processes regulating calcium homeostasis.

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Mechanism of β2AR regulation by an intracellular positive allosteric modulator

Science ◽

10.1126/science.aaw8981 ◽

2019 ◽

Vol 364 (6447) ◽

pp. 1283-1287 ◽

Cited By ~ 14

Author(s):

Xiangyu Liu ◽

Ali Masoudi ◽

Alem W. Kahsai ◽

Li-Yin Huang ◽

Biswaranjan Pani ◽

...

Keyword(s):

G Protein ◽

Adrenergic Receptor ◽

Helical Conformation ◽

Allosteric Modulator ◽

Intracellular Loop ◽

Positive Allosteric Modulator ◽

Transmembrane Segments ◽

Allosteric Binding Sites ◽

Loop 2 ◽

G Protein Coupled

Drugs targeting the orthosteric, primary binding site of G protein–coupled receptors are the most common therapeutics. Allosteric binding sites, elsewhere on the receptors, are less well-defined, and so less exploited clinically. We report the crystal structure of the prototypic β2-adrenergic receptor in complex with an orthosteric agonist and compound-6FA, a positive allosteric modulator of this receptor. It binds on the receptor’s inner surface in a pocket created by intracellular loop 2 and transmembrane segments 3 and 4, stabilizing the loop in an α-helical conformation required to engage the G protein. Structural comparison explains the selectivity of the compound for β2- over the β1-adrenergic receptor. Diversity in location, mechanism, and selectivity of allosteric ligands provides potential to expand the range of receptor drugs.

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Understanding allosteric interactions in G protein-coupled receptors using Supervised Molecular Dynamics: A prototype study analysing the human A3 adenosine receptor positive allosteric modulator LUF6000

Bioorganic & Medicinal Chemistry ◽

10.1016/j.bmc.2015.03.039 ◽

2015 ◽

Vol 23 (14) ◽

pp. 4065-4071 ◽

Cited By ~ 33

Author(s):

Giuseppe Deganutti ◽

Alberto Cuzzolin ◽

Antonella Ciancetta ◽

Stefano Moro

Keyword(s):

Molecular Dynamics ◽

G Protein ◽

Adenosine Receptor ◽

G Protein Coupled Receptors ◽

Allosteric Modulator ◽

Positive Allosteric Modulator ◽

Allosteric Interactions ◽

A3 Adenosine Receptor ◽

G Protein Coupled

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A nanobody activating metabotropic glutamate receptor 4 discriminates between homo- and heterodimers

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2105848118 ◽

2021 ◽

Vol 118 (33) ◽

pp. e2105848118

Author(s):

Jordi Haubrich ◽

Joan Font ◽

Robert B. Quast ◽

Anne Goupil-Lamy ◽

Pauline Scholler ◽

...

Keyword(s):

Small Molecules ◽

Metabotropic Glutamate Receptor ◽

Brain Diseases ◽

Allosteric Modulator ◽

Receptor Subtypes ◽

Positive Allosteric Modulator ◽

Metabotropic Glutamate ◽

Glutamate Binding ◽

Subtype Selective ◽

G Protein Coupled

There is growing interest in developing biologics due to their high target selectivity. The G protein–coupled homo- and heterodimeric metabotropic glutamate (mGlu) receptors regulate many synapses and are promising targets for the treatment of numerous brain diseases. Although subtype-selective allosteric small molecules have been reported, their effects on the recently discovered heterodimeric receptors are often not known. Here, we describe a nanobody that specifically and fully activates homodimeric human mGlu4 receptors. Molecular modeling and mutagenesis studies revealed that the nanobody acts by stabilizing the closed active state of the glutamate binding domain by interacting with both lobes. In contrast, this nanobody does not activate the heterodimeric mGlu2-4 but acts as a pure positive allosteric modulator. These data further reveal how an antibody can fully activate a class C receptor and bring further evidence that nanobodies represent an alternative way to specifically control mGlu receptor subtypes.

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