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Conformational Constraint of Mammalian, Chicken, and Salmon GnRHs, But Not GnRH II, Enhances Binding at Mammalian and Nonmammalian Receptors: Evidence for Preconfiguration of GnRH II

Medical Research Council Human Reproductive Sciences Unit (K.D.G.P., R.P.M.), Edinburgh, EH16 4SB, United Kingdom; and Department of Endocrinology (J.B.), Utrecht University, 3508 TB, Utrecht, The Netherlands

Address all correspondence and requests for reprints to: Robert P. Millar, Director, Medical Research Council Human Reproductive Sciences Unit, Edinburgh, EH16 4SB, United Kingdom. E-mail: r.millar{at}hrsu.mrc.ac.uk.

Mammalian GnRH (mGnRH) is believed to interact with mGnRH type I receptors in a ß-II' turn conformation involving residues 5–8. This conformation can be constrained by substitution of a D-amino acid at position 6 or by a lactam ring involving residues 6 and 7, thereby increasing receptor binding affinity. It has been proposed that this is not the case for non-mGnRH 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-mGnRH as well as mGnRH type I receptors. In contrast, most substitutions of a D-amino acid in position 6 have limited effect on binding affinity for GnRH II. We suggest that this ligand is preconfigured 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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