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Vol. 60, Issue 6, 1280-1287, December 2001
Division of Medical Biochemistry (B.J.F., A.A.K., R.P.M., C.A.F.)
and Department of Medicine (C.A.F.), University of Cape Town Faculty of
Health Sciences, Observatory, South Africa; Indiana University School
of Medicine, Indianapolis, Indiana (R.W.R.); and Medical Research
Council Human Reproductive Sciences Unit, Edinburgh, Scotland, UK
(R.P.M.)
Mammalian gonadotropin-releasing hormone (GnRH) receptors
preferentially bind mammalian GnRH, which has Arg in position eight. The Glu7.32(301) residue, which determines selectivity of
the mouse GnRH receptor for Arg8-containing GnRH, is
Asp7.32(302) in the human GnRH receptor. We have confirmed
that Asp7.32(302) confers selectivity of the human GnRH
receptor for Arg8 of GnRH and investigated the mechanism of
this specificity using site-directed mutagenesis and ligand
modification. We find that although Arg8 and
Asp7.32(302) are required for high-affinity binding of
GnRH, conformationally constrained peptides, with D-amino
acid substitutions in position six or with a 6,7 
-lactam, bind the
human GnRH receptor with high affinity, which is independent of the
presence of Asp7.32(302) in the receptor or
Arg8 in the ligand. The ability of the ligand constraints
to compensate for the absence of both Arg8 and
Asp7.32(302) indicates that these residues both have roles
in stabilizing a high affinity ligand conformation and that their roles
are complementary. This suggests that the Arg8 and
Asp7.32(302) side chains interact to induce a high affinity
conformation of native GnRH. Thus, Asp7.32(302) of the
human GnRH receptor determines selectivity for mammalian GnRH by its
ability to induce a high affinity conformation of its native ligand.
However, this initial interaction seems not to contribute to the final
ligand-receptor complex. We propose that Arg8 interacts
transiently with Asp7.32(302) to induce a high-affinity
ligand conformation of GnRH, which then interacts with a binding pocket
that is common for both constrained and unconstrained analogs of GnRH.
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