Identification of Tyr290(6.58) of the human gonadotropin- releasing hormone (GnRH) receptor as a contact residue for both GnRH I and GnRH II: Importance for high-affinity binding and receptor activation

Marla Coetsee, Robert P. Millar, Colleen A. Flanagan, Zhi Liang Lu*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

18 Citations (Scopus)


Molecular modeling showed interactions of Tyr290(6.58) in transmembrane domain 6 of the GnRH receptor with Tyr5 of GnRH I, and His5 of GnRH II. The wild-type receptor exhibited high affinity for [Phe5]GnRH I and [Tyr5]GnRH II, but 127- and 177-fold decreased affinity for [Ala5]GnRH I and [Ala5]GnRH II, indicating that the aromatic ring in position 5 is crucial for receptor binding. The receptor mutation Y290F decreased affinity for GnRH I, [Phe 5]GnRH I, GnRH II and [Tyr5]GnRH II, while Y290A and Y290L caused larger decreases, suggesting that both the para-OH and aromatic ring of Tyr290(6.58) are important for binding of ligands with aromatic residues in position 5. Mutating Tyr290(6.58) to Gln increased affinity for Tyr5-containing GnRH analogues 3-12-fold compared with the Y290A and Y290L mutants, suggesting a hydrogen-bond between Gln of the Y290Q mutant and Tyr5 of GnRH analogues. All mutations had small effects on affinity of GnRH analogues that lack an aromatic residue in position 5. These results support direct interactions of the Tyr290(6.58) side chain with Tyr5 of GnRH I and His5 of GnRH II. Tyr 290(6.58) mutations, except for Y290F, caused larger decreases in GnRH potency than affinity, indicating that an aromatic ring is important for the agonist-induced receptor conformational switch.

Original languageEnglish
Pages (from-to)10305-10313
Number of pages9
Issue number39
Publication statusPublished - 30 Sept 2008
Externally publishedYes

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