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Volume 271, Number 49, Issue of December 6, 1996 pp. 31593-31601
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.

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Separate Agonist and Peptide Antagonist Binding Sites of the Oxytocin Receptor Defined by Their Transfer into the V₂ Vasopressin Receptor

(Received for publication, July 29, 1996, and in revised form, September 19, 1996)

From the Max-Planck-Institut für Biophysik, Kennedyallee 70, 60596  Frankfurt am Main, Federal Republic of Germany

The neurohypophyseal nonapeptide oxytocin (OT) is the main hormone responsible for the initiation of labor; uterus contraction can be enhanced by application of oxytocin or suppressed by oxytocin antagonists. By transfer of domains from the G protein-coupled OT receptor into the related V₂ vasopressin receptor, chimeric "gain in function" V₂/OT receptors were produced that were able to bind either OT receptor agonists or a competitive peptide antagonist with high affinity. The binding site for the OT antagonist d(CH₂)₅[Tyr(Me)²,Thr⁴,Orn⁸,Tyr⁹]vasotocin was found to be formed by transmembrane helices 1, 2, and 7 with a major contribution to binding affinity by the upper part of helix 7. These transmembrane receptor regions could be excluded from participating in OT binding. For agonist binding and selectivity the first three extracellular receptor domains were most important. The interaction of the N-terminal domain and of the first extracellular loop of the OT receptor with the linear C-terminal tripeptidic part of oxytocin was demonstrated. Furthermore, the second extracellular loop of the OT receptor could be identified to interact with the cyclic hormone part. These three domains contribute to OT binding by synergistic interaction with oxytocin but not with the competitive antagonist. Our results provide evidence for the existence of separate domains and different conformations of a peptide hormone receptor involved in binding and selectivity for agonists and peptide antagonists.

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