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  • Title: Overlapping, nonidentical binding sites of different classes of nonpeptide antagonists for the human gonadotropin-releasing hormone receptor.
    Author: Betz SF, Reinhart GJ, Lio FM, Chen C, Struthers RS.
    Journal: J Med Chem; 2006 Jan 26; 49(2):637-47. PubMed ID: 16420049.
    Abstract:
    Peptide agonists and antagonists of the human gonadotropin-releasing hormone receptor (GnRH-R) are widely used to treat a range of reproductive hormone related diseases. Recently, nonpeptide, orally available GnRH-R antagonists have emerged from several chemical classes. To understand how a relatively large peptide-binding pocket can recognize numerous nonpeptide ligands, we undertook a systematic mapping of GnRH-R residues involved in the binding of three nonpeptide antagonists. A region composed of the extracellular portions of transmembrane helices 6 and 7, extracellular loop 3, and the N-terminal domain significantly contributed to nonpeptide antagonist binding. However, each molecule was affected by a different subset of residues in these regions, indicating that each appears to occupy distinct, partially overlapping subregions within the more extensive peptide-binding pocket. Moreover, the resulting receptor interaction maps provide a basis to begin to reconcile structure-activity relationships between various nonpeptide and peptide series and facilitate the design of improved therapeutic agents.
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