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(Received for publication, March 4, 1996, and in revised form, April 5, 1996)
From the We demonstrate a critical role for
Asn102 of the human gonadotropin-releasing hormone (GnRH)
receptor in the binding of GnRH. Mutation of Asn102,
located at the top of the second transmembrane helix, to Ala resulted
in a 225-fold loss of potency for GnRH. Eight GnRH analogs, all
containing glycinamide C termini like GnRH, showed similar losses of
potency between 95- and 750-fold for the [Ala102]GnRHR,
compared with wild-type receptor. In contrast, four GnRH analogs that
had ethylamide in place of the C-terminal glycinamide residue, showed
much smaller decreases in potency between 2.4- and 11-fold. In
comparisons of three agonist pairs, differing only at the C terminus,
glycinamide derivatives showed an 11-20-fold greater loss of potency
for the mutant receptor than their respective ethylamide derivatives.
Thus Asn102 is a critical determinant of potency
specifically for ligands with C-terminal glycinamide, while ligands
with C-terminal ethylamide are less dependent on Asn102.
These findings indicate a role for Asn102 in the docking of
the glycinamide C terminus and are consistent with hydrogen bonding of
the Asn102 side chain with the C-terminal amide moiety.
Taken with previous data, they suggest a region of the GnRH receptor
formed by the top of helices 2 and 7 as a binding pocket for the
C-terminal part of the ligand.
Volume 271, Number 26,
Issue of June 28, 1996
pp. 15510-15514
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.
,
,
,
and
Medical Research Council Regulatory Peptides
Research Unit, Department of Chemical Pathology, University of Cape
Town Medical School, Observatory 7925, South Africa, the
¶ Department of Medicine, University of Bristol, Bristol BS2
8HW, United Kingdom, and the 
Endocrine Laboratory, Department of
Medicine, University of Cape Town Medical School, Observatory 7925, South Africa
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