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A Locus of the Gonadotropin-releasing Hormone Receptor That Differentiates Agonist and Antagonist Binding Sites (∗)

Journal of Biological Chemistry, ISSN: 0021-9258, Vol: 270, Issue: 32, Page: 18853-18857
1995
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The decapeptide gonadotropin-releasing hormone controls reproductive function via interaction with a heptahelical G protein-coupled receptor. Because a molecular model of the receptor predicts that Lys 121 in the third transmembrane helix contributes to the binding pocket, the function of this side chain was studied by site-directed mutagenesis. Substitution of Arg at this position preserved high affinity agonist binding, whereas Gln at this position reduced binding below the limits of detection. Leu and Asp at this locus abolished both binding and detectable signal transduction. The EC 50 of concentration-response curves for coupling to phosphatidyl inositol hydrolysis obtained with the Gln 121 receptor was more than 3 orders of magnitude higher than that obtained for the wild-type receptor. In order to determine whether the increased EC 50 obtained with this mutant reflects an altered receptor affinity, the effect of decreases in wild-type receptor density on concentration-response curves was determined by irreversible antagonism. Progressively decreasing the concentration of the wild-type receptor increased the EC 50 values obtained to a maximal level of 2.4 ± 0.2 nM. Comparison of this value with the EC 50 of 282 ± 52 nM observed with the Gln 121 receptor mutant indicates that the agonist affinity for this mutant is reduced more than 100-fold. In contrast, antagonist had comparable high affinities for the wild-type, Arg 121, and Gln 121 mutants. The results indicate that a charge-strengthened hydrogen bond donor is required at this locus for high affinity agonist binding but not for high affinity antagonist binding.

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