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Identification of a novel ligand binding residue Arg38(1.35) in the human gonadotropin-releasing hormone receptor

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Alan J. Stewart, Robin Sellar, Donald J. Wilson, Robert P. Millar, Zhi-Liang Lu

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Delineation of peptide ligand binding sites is of fundamental importance in rational drug design and in understanding ligand-induced receptor activation. Molecular modeling and ligand docking to previously experimentally identified binding sites revealed a putative novel interaction between the C terminus of gonadotropin-releasing hormone (GnRH) and Arg38(1.35), located at the extracellular end of transmembrane domain 1 of the human GnRH receptor. Mutation of Arg38(1.35) to alanine resulted in 989- and 1268-fold reduction in affinity for GnRH I and GnRH II, respectively, the two endogenous ligands. Conservative mutation of Arg38(1.35) to lysine had less effect, giving reduced affinities of GnRH I and GnRH II by 24- and 54-fold, respectively. To test whether Arg38(1.35) interacts with the C-terminal Gly10-NH2 of GnRH, binding of GnRH analogs with substitution of the C-terminal glycinamide with ethylamide ([Pro9-NHEt]GnRH) was studied with wild-type and Arg38(1.35) mutant receptors. Mutation of Arg38(1.35) to lysine or alanine had much smaller effect on receptor affinity for [Pro9-NHEt]GnRH analogs and no effect on binding affinity of peptide antagonist cetrorelix. In parallel with the decreased affinity, the mutants also gave a decreased potency to GnRH-elicited inositol phosphate (IP) responses. The mutant receptors had effects on [Pro9-NHEt]GnRH-elicited IP responses similar to that of the parent GnRHs. These findings indicate that Arg38(1.35) of the GnRH receptor is essential for high-affinity binding of GnRH agonists and stabilizing the receptor active conformation. The mutagenesis results support the prediction of molecular modeling that Arg38(1.35) interacts with the C-terminal glycinamide and probably forms hydrogen bonds with the backbone carbonyl of Pro9 and Gly10-NH2.



Original languageEnglish
Pages (from-to)75-81
Number of pages7
JournalMolecular Pharmacology
Issue number1
Early online date17 Oct 2007
Publication statusPublished - Jan 2008

    Research areas

  • Protein-coupled-receptor, Human oxytocin receptor, GNRH receptor, Agonist binding, 7-transmembrane receptors, Muscarinic receptor, Antagonist binding, Affinity, Cells, Switch

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