Tyr115 is the key residue for determining agonist selectivity in the V1a vasopressin receptor

Using a three‐dimensional model of G protein‐coupled receptors (GPCR), we have previously succeeded in docking the neurohypophysial hormone arginine‐vasopressin (AVP) into the V1a receptor. According to this model, the hormone is completely embedded in the transmembrane part of the receptor. Only th...

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Bibliographic Details
Published in:The EMBO journal 1995-05, Vol.14 (10), p.2176-2182
Main Authors: Chini, B., Mouillac, B., Ala, Y., Balestre, M.N., Trumpp‐Kallmeyer, S., Hoflack, J., Elands, J., Hibert, M., Manning, M., Jard, S.
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Animals
Arginine Vasopressin - analogs & derivatives
Binding Sites - genetics
Dose-Response Relationship, Drug
Humans
Ligands
Models, Molecular
Molecular Sequence Data
Oligopeptides - metabolism
Rats
Receptors, Oxytocin - genetics
Receptors, Oxytocin - metabolism
Receptors, Vasopressin - agonists
Receptors, Vasopressin - chemistry
Receptors, Vasopressin - genetics
Signal Transduction
Structure-Activity Relationship
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Summary:Using a three‐dimensional model of G protein‐coupled receptors (GPCR), we have previously succeeded in docking the neurohypophysial hormone arginine‐vasopressin (AVP) into the V1a receptor. According to this model, the hormone is completely embedded in the transmembrane part of the receptor. Only the side chain of the Arg residue at position 8 projects outside the transmembrane core of the receptor and possibly interacts with a Tyr residue located in the first extracellular loop at position 115. Residue 8 varies in the two natural neurohypophysial hormones, AVP and oxytocin (OT); similarly, different residues are present at position 115 in the different members of the AVP/OT receptor family. Here we show that Arg8 is crucial for high affinity binding of AVP to the rat V1a receptor. Moreover, when Tyr115 is replaced by an Asp and a Phe, the amino acids naturally occurring in the V2 and in the OT receptor subtypes, the agonist selectivity of the V1a receptor switches accordingly. Our results indicate that the interaction between peptide residue 8 and the receptor residue at position 115 is not only crucial for agonist high affinity binding but also for receptor selectivity.
ISSN:0261-4189
1460-2075
DOI:10.1002/j.1460-2075.1995.tb07211.x