Agonist-specific requirement for a glutamate in transmembrane helix 1 of the oxytocin receptor

Denise L. Wootten, John Simms, Amelia J. Massoura, Julie E. Trim, Mark Wheatley*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


Defining key differences between agonist and antagonist binding to hormone receptors is important and will aid rational drug design. Glu1.35 in transmembrane helix 1 (TM1) of the human oxytocin receptor (OTR) is absolutely conserved in all OTRs cloned to date. We establish that Glu1.35 is critical for high affinity binding of agonists (full and partial) but is not required for antagonist binding (peptide or non-peptide). Consequently, the mutant receptor [E1.35A]OTR exhibited markedly decreased OT affinity (>1200-fold) and disrupted second messenger generation. Substitutions of Glu1.35 by Asp, Gln or Arg were incapable of supporting wild-type OTR agonist binding or signaling. Molecular modeling revealed that Glu1.35 projects into the receptor's central binding crevice and provides agonist-specific contacts not utilized by antagonists. This study explains why Glu is absolutely conserved at residue-1.35 in all receptors binding OT and related peptides, and provides molecular insight into key differences between agonist-receptor and antagonist-receptor binding modes.

Original languageEnglish
Pages (from-to)20-27
Number of pages8
JournalMolecular and Cellular Endocrinology
Issue number1
Publication statusPublished - 10 Feb 2011


  • GPCR
  • Oxytocin
  • Oxytocin receptor
  • Peptide hormone


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