Histidine7.36(305) in the conserved peptide receptor activation domain of the gonadotropin releasing hormone receptor couples peptide binding and receptor activation

Nkateko M.I. Mayevu, Han Choe, Ruben Abagyan, Jae Young Seong, Robert P. Millar, Arieh A. Katz, Colleen A. Flanagan

Research output: Contribution to journalArticlepeer-review

4 Citations (Scopus)

Abstract

Transmembrane helix seven residues of G protein-coupled receptors (GPCRs) couple agonist binding to a conserved receptor activation mechanism. Amino-terminal residues of the GnRH peptide determine agonist activity. We investigated GnRH interactions with the His7.36(305) residue of the GnRH receptor, using functional and computational analysis of modified GnRH receptors and peptides. Non-polar His7.36(305) substitutions decreased receptor affinity for GnRH four- to forty-fold, whereas GnRH signaling potency was more decreased (~150-fold). Uncharged polar His7.36(305) substitutions decreased GnRH potency, but not affinity. [2-Nal3]-GnRH retained high affinity at receptors with non-polar His7.36(305) substitutions, supporting a role for His7.36(305) in recognizing Trp3 of GnRH. Compared with GnRH, [2-Nal3]-GnRH potency was lower at the wild type GnRH receptor, but unchanged or higher at mutant receptors. Results suggest that His7.36(305) of the GnRH receptor forms two distinct interactions that determine binding to Trp3 and couple agonist binding to the conserved transmembrane domain network that activates GPCRs.

Original languageEnglish
Pages (from-to)95-106
Number of pages12
JournalMolecular and Cellular Endocrinology
Volume402
DOIs
Publication statusPublished - 2015 Feb 5

Keywords

  • G protein-coupled receptor (GPCR)
  • GnRH
  • Hormone receptor
  • Peptide hormone
  • Peptide interaction
  • Receptor structure-function

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Endocrinology

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