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.
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February 2003
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Conference Article|
February 01 2003
Agonist binding to peptide hormone receptors
M. Wheatley;
M. Wheatley
1
School of Biosciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, U.K.
1To whom correspondence should be addressed (e-mail m.wheatley@bham.ac.uk).
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S.R. Hawtin;
S.R. Hawtin
School of Biosciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, U.K.
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V.J. Wesley;
V.J. Wesley
School of Biosciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, U.K.
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H.C. Howard;
H.C. Howard
School of Biosciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, U.K.
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J. Simms;
J. Simms
School of Biosciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, U.K.
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A. Miles;
A. Miles
School of Biosciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, U.K.
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K. McEwan;
K. McEwan
School of Biosciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, U.K.
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R.A. Parslow
R.A. Parslow
School of Biosciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, U.K.
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Publisher: Portland Press Ltd
Online ISSN: 1470-8752
Print ISSN: 0300-5127
Copyright 2003 Biochemical Society
2003
Biochem Soc Trans (2003) 31 (1): 35–39.
Citation
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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