A Single Residue (Arg46) Located Within the N-Terminus of the V1aVasopressin Receptor Is Critical for Binding Vasopressin But Not Peptide or Nonpeptide Antagonists
| Autor: | Rosemary A. Parslow, Kim McEwan, Mark Wheatley, Stuart R. Hawtin, John Simms, Victoria J Wesley, Alice Miles |
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| Rok vydání: | 2002 |
| Předmět: |
Agonist
Receptors Vasopressin Vasopressin Vasopressins medicine.drug_class Molecular Sequence Data Biology Arginine Transfection Tritium Second Messenger Systems Cell Line Radioligand Assay Structure-Activity Relationship Endocrinology Arginine vasopressin receptor 2 medicine Animals Humans Amino Acid Sequence Binding site Receptor Molecular Biology Vasopressin receptor G protein-coupled receptor Arginine vasopressin receptor 1B Binding Sites General Medicine Rats Arginine Vasopressin Biochemistry Mutagenesis |
| Zdroj: | Molecular Endocrinology. 16:600-609 |
| ISSN: | 1944-9917 0888-8809 |
| Popis: | A fundamental issue in molecular endocrinology is to define how agonist:receptor interaction differs from antagonist:receptor interaction. The vasopressin V1a receptor (V1aR) is a member of a subfamily of related G protein-coupled receptors that are activated by the hormone AVP or related peptides. The N-terminus of the V1aR has recently been shown to be critical for binding agonists but not antagonists. Using a combination of N-terminally truncated constructs and alanine-scanning mutagenesis, individual residues that provide these agonist-specific binding epitopes have now been identified in this study. Our data establish that a single residue, Arg46, is critical for AVP binding to the V1aR. Systematic substitution revealed that Arg was required at this locus and could not be substituted by Lys, Glu, Leu, or Ala. In contrast, antagonist binding (cyclic or linear, peptide or nonpeptide) was unaffected. Disruption of Arg46 also resulted in defective intracellular signaling. Arginine is conserved at this locus in all members of the neurohypophysial peptide hormone receptor family cloned to date, indicative of a fundamental role in receptor function. In addition to Arg46, the residues Leu42, Gly43, Asp45 form a patch contributing to AVP binding. This study provides molecular insight into the role of the V1aR N-terminus and key differences between agonist and antagonist binding requirements. |
| Databáze: | OpenAIRE |
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