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 mo del, the hormone is completely embedded in the transmembrane part of t he receptor. Only the side chain of the Arg residue at position 8 proj ects outside the transmembrane core of the receptor and possibly inter acts with a Tyr residue located in the first extracellular loop at pos ition 115. Residue 8 varies in the two natural neurohypophysial hormon es, AVP and oxytocin (OT); similarly, different residues are present a t 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 re ceptor 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 crucia l for agonist high affinity binding but also for receptor selectivity.