Histidine(7.36(305)) in the conserved peptide receptor activation domain of the gonadotropin releasing hormone receptor couples peptide binding and receptor activation.
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 His(7.36(305)) residue of the GnRH receptor, using functional and computational analysis of modified GnRH receptors and peptides. Non-polar His(7.36(305)) substitutions decreased receptor affinity for GnRH four- to forty-fold, whereas GnRH signaling potency was more decreased (~150-fold). Uncharged polar His(7.36(305)) substitutions decreased GnRH potency, but not affinity. [2-Nal(3)]-GnRH retained high affinity at receptors with non-polar His(7.36(305)) substitutions, supporting a role for His(7.36(305)) in recognizing Trp(3) of GnRH. Compared with GnRH, [2-Nal(3)]-GnRH potency was lower at the wild type GnRH receptor, but unchanged or higher at mutant receptors. Results suggest that His(7.36(305)) of the GnRH receptor forms two distinct interactions that determine binding to Trp(3) and couple agonist binding to the conserved transmembrane domain network that activates GPCRs.
['Mayevu|Nkateko M I|NM|', 'Choe|Han|H|', 'Abagyan|Ruben|R|', 'Seong|Jae Young|JY|', 'Millar|Robert P|RP|', 'Katz|Arieh A|AA|', 'Flanagan|Colleen A|CA|']
D000595:Amino Acid Sequence D000818:Animals D001667:Binding, Competitive D019556:COS Cells D002522:Chlorocebus aethiops D017124:Conserved Sequence D007987:Gonadotropin-Releasing Hormone D006639:Histidine D007295:Inositol Phosphates D051379:Mice D008958:Models, Molecular D011485:Protein Binding D054730:Protein Interaction Domains and Motifs D011966:Receptors, LHRH D015398:Signal Transduction
Hormone receptor G protein-coupled receptor (GPCR) GnRH Peptide hormone Peptide interaction Receptor structure-function