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- W2584604256 abstract "Abstract Characterisation of G protein-coupled receptors (GPCR) relies on the availability of a toolbox of ligands that selectively modulate different functional states of the receptors. To uncover such molecules, we explored a unique strategy for ligand discovery that takes advantage of the evolutionary conservation of the 600-million-year-old oxytocin/vasopressin signalling system. We isolated the insect oxytocin/vasopressin orthologue inotocin from the black garden ant ( Lasius niger ), identified and cloned its cognate receptor and determined its pharmacological properties on the insect and human oxytocin/vasopressin receptors. Subsequently, we identified a functional dichotomy: inotocin activated the insect inotocin and the human vasopressin V 1b receptors, but inhibited the human V 1a R. Replacement of Arg8 of inotocin by D-Arg8 led to a potent, stable and competitive V 1a R-antagonist ([D-Arg8]-inotocin) with a 3,000-fold binding selectivity for the human V 1a R over the other three subtypes, OTR, V 1b R and V 2 R. The Arg8/D-Arg8 ligand-pair was further investigated to gain novel insights into the oxytocin/vasopressin peptide-receptor interaction, which led to the identification of key residues of the receptors that are important for ligand functionality and selectivity. These observations could play an important role for development of oxytocin/vasopressin receptor modulators that would enable clear distinction of the physiological and pathological responses of the individual receptor subtypes." @default.
- W2584604256 created "2017-02-10" @default.
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- W2584604256 date "2017-02-01" @default.
- W2584604256 modified "2023-10-13" @default.
- W2584604256 title "Development of a human vasopressin V1a-receptor antagonist from an evolutionary-related insect neuropeptide" @default.
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- W2584604256 doi "https://doi.org/10.1038/srep41002" @default.
- W2584604256 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/5286520" @default.
- W2584604256 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/28145450" @default.
- W2584604256 hasPublicationYear "2017" @default.
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