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J. Biol. Chem., Vol. 280, Issue 46, 38569-38575, November 18, 2005

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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**, and Robert P. Millar¶1

From the School of Chemistry, The University of Edinburgh, Edinburgh EH9 3JJ, United Kingdom, School of Medicine, Indiana University, Indiana 46202-5122, ^¶MRC Human Reproductive Sciences Unit, Centre for Reproductive Biology, The Queen's Medical Research Institute, Edinburgh EH16 4TJ, United Kingdom, ^||Department of Chemistry and Biochemistry, University of California, Santa Barbara, California 93106-9510, ^**Department of Life Science, Himeji Institute of Technology, Hyogo 678-1297, Japan, and Department of Medical Biochemistry, University of Cape Town, Observatory 7925, Cape Town, South Africa

Gonadotropin-releasing hormone (GnRH) is the central regulator of reproduction in vertebrates. GnRHs have recently been identified in protochordates 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' -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 that 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' -turn. Structural analysis of the GnRHs using ion mobility-mass spectrometry and molecular modeling showed a greater propensity for a type II' -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.

Received for publication, March 21, 2005 , and in revised form, August 11, 2005.

^* This work was supported by the Engineering and Physical Sciences Research Council (to P. E. B.), the Medical Research Councils of the United Kingdom and South Africa (to R. P. M.), and the National Science Foundation (to M. T. B.) for support. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed. Tel.: 441312426240; Fax: 441312426231; E-mail: r.millar{at}hrsu.mrc.ac.uk.

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				P.-S. Tsai and L. Zhang The Emergence and Loss of Gonadotropin-Releasing Hormone in Protostomes: Orthology, Phylogeny, Structure, and Function Biol Reprod, November 1, 2008; 79(5): 798 - 805. [Abstract] [Full Text] [PDF]

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