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Submitted on April 30, 2002
Accepted on June 10, 2002
1 MRC Human Reproductive Sciences Unit (K.D.G.P., R.P.M.), 37 Chalmers Street, Edinburgh, EH3 9ET, UK; Department of Endocrinology (J.B.), Utrecht University, PO Box 80058, 3508 TB, Utrecht, The Netherlands.
* To whom correspondence should be addressed. E-mail: r.millar{at}hrsu.mrc.ac.uk.
Mammalian GnRH (mGnRH) is believed to interact with mammalian GnRH receptors in a ß-II' turn conformation involving residues five to eight. This conformation can be constrained by substitution of a D-amino acid at position six or by a lactam ring involving residues six and seven, thereby increasing receptor binding affinity. It has been proposed that this is not the case for non-mammalian GnRH receptors. However, we show that this conformational constraint increases the binding affinity of mammalian, chicken and salmon GnRH for the chicken and catfish receptors, as well as for the mouse receptor. Therefore, we conclude that the ß-II' turn conformation enhances ligand binding for non-mammalian as well as mammalian GnRH receptors. In contrast, most substitutions of a D-amino acid in position six have limited effect on binding affinity for GnRH II. We suggest that this ligand is pre-configured through intramolecular interactions, which accounts for its high binding affinity and total conservation of primary structure over 500 million years of evolution.
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