TAILIEUCHUNG - Báo cáo khoa học: An arginyl in the N-terminus of the V1a vasopressin receptor is part of the conformational switch controlling activation by agonist

Defining how the agonist–receptor interaction differs from that of the antagonist–receptor and understanding the mechanisms of receptor activation are fundamental issues in cell signalling. The V1a vasopressin receptor (V1aR) is a member of a family of related G-protein coupled receptors that are activated by neurohypophysial peptide hormones, including vasopressin (AVP). It has recently been reported that anarginyl in the distalN-terminus of theV1a Riscritical for binding agonists but not antagonists | Eur. J. Biochem. 270 4681-4688 2003 FEBS 2003 doi An arginyl in the N-terminus of the V1a vasopressin receptor is part of the conformational switch controlling activation by agonist Stuart R. Hawtin1 I Victoria J. Wesley1 John Simms1 Rosemary A. Parslow1 Alice Miles1 Kim McEwan1 Mary Keen2 and Mark Wheatley1 1 School of Biosciences and department of Pharmacology Division of Neuroscience The Medical School University of Birmingham Edgbaston Birmingham UK Defining how the agonist-receptor interaction differs from that of the antagonist-receptor and understanding the mechanisms of receptor activation are fundamental issues in cell signalling. The V1a vasopressin receptor V1aR is a member of a family of related G-protein coupled receptors that are activated by neurohypophysial peptide hormones including vasopressin AVP . It has recently been reported that an arginyl in the distal N-terminus of the V1aR is critical for binding agonists but not antagonists. To determine specific features required at this locus to support high affinity agonist binding and second messenger generation Arg46 was substituted by all other 19 encoded amino acids. Our data establish that there is an absolute requirement for arginyl as none of the R46X V 1aR mutant constructs supported high affinity agonist binding and all 19 had defective signalling. In contrast all of the mutant receptors possessed wildtype binding for both peptide and nonpeptide antagonists. The ratio of Ki to EC50 an indicator of efficacy was increased for all substitutions. Consequently although R46X V1aR constructs have a lower affinity for agonist once AVP has bound all 19 are more likely than the wildtype V1aR to become activated. Therefore in the wildtype V1aR Arg46 constrains the inactive conformation of the receptor. On binding AVP this constraint is alleviated promoting the transition to active V 1aR. Our findings explain why arginyl is conserved at this locus throughout the .

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