Evolution of constrained gonadotropin-releasing hormone ligand conformation and receptor selectivity

Perdita E. Barran, Roger W. Roeske, Adam J. Pawson, Robin Sellar, Michael T. Bowers, Kevin Morgan, Zhi Liang Lu, Motoyuki Tsuda, Takehiro Kusakabe, Robert P. Millar*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

34 Citations (Scopus)

Abstract

Gonadotropin-releasing hormone (GnRH) is the central regulator of reproduction in vertebrates. GnRHs have recently been identified inprotochordates and retain the conserved N- and C-terminal domains involved in receptor binding and activation. GnRHs of the jawed vertebrates have a central achiral amino acid (glycine) that favors a type II′ β-turn such that the N- and C-terminal domains are closely apposed in binding the GnRH receptor. However, protochordate GnRHs have a chiral amino acid in this position, suggesting hat they bind their receptors in a more extended form. We demonstrate here that a protochordate GnRH receptor does not distinguish GnRHs with achiral or chiral amino acids, whereas GnRH receptors of jawed vertebrates are highly selective for GnRHs with the central achiral glycine. The poor activity of the protochordate GnRH was increased > 10-fold at vertebrate receptors by replacement of the chiral amino acid with glycine or a D-amino acid, which favor the type II′ β-turn. Structural analysis of the GnRHs using ion mobility-mass spectrometry and molecular modeling showed a greater propensity for a type II′ β-turn in GnRHs with glycine or a D-amino acid, which correlates with binding affinity at vertebrate receptors. These findings indicate that the substitution of glycine for a chiral amino acid in GnRH during evolution allows a more constrained conformation for receptor binding and that this subtle single amino acid substitution in a site remote from the ligand functional domains has marked effects on its structure and activity.

Original languageEnglish
Pages (from-to)38569-38575
Number of pages7
JournalJournal of Biological Chemistry
Volume280
Issue number46
DOIs
Publication statusPublished - 2005
Externally publishedYes

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