A fundamental issue in molecular pharmacology is to define how agonist–receptor interaction differs from that of antagonist–receptor interaction. The V1a vasopressin receptor (V1aR) is a member of a family of related G-protein-coupled receptors (GPCRs) that are activated by vasopressin, oxytocin (OT) and related peptides. A segment of the N-terminus that was required for agonist binding, but not antagonist binding, was identified by characterizing truncated V1aR constructs. Site-directed mutagenesis revealed that a single residue (Arg46) was critical for agonist binding and receptor activation. The N-terminus of the related OT receptor (OTR) could recover agonist binding in a chimaeric OTRN–V1aR construct. Furthermore, Arg34 of the human OTR, which corresponds to Arg46 of the rat V1aR, provided agonist-specific binding epitopes in the OTR, indicating a conserved function of this locus throughout this GPCR subfamily. Mutation of Arg46 revealed that high-affinity agonist binding had an absolute requirement for arginine at this position.
Agonist binding to peptide hormone receptors
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M. Wheatley, S.R. Hawtin, V.J. Wesley, H.C. Howard, J. Simms, A. Miles, K. McEwan, R.A. Parslow; Agonist binding to peptide hormone receptors. Biochem Soc Trans 1 February 2003; 31 (1): 35–39. doi: https://doi.org/10.1042/bst0310035
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