title: Overlapping, nonidentical binding sites of different classes of nonpeptide antagonists for the human gonadotropin-releasing hormone receptor.
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.
authors.affiliation: Department of Endocrinology, Neurocrine Biosciences, Inc., San Diego, California 92130, USA. sbetz@neurocrine.com
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Betz
authors.forename: Greg J
authors.initials: GJ
authors.lastname: Reinhart
authors.forename: Francisco M
authors.initials: FM
authors.lastname: Lio
authors.forename: Chen
authors.initials: C
authors.lastname: Chen
authors.forename: R Scott
authors.initials: RS
authors.lastname: Struthers
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D019556:COS Cells; D002522:Chlorocebus aethiops; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology*; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D010455:Peptides / Q000737:chemistry; D010671:Phenylurea Compounds / Q000737:chemistry / Q000494:pharmacology*; D017354:Point Mutation; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011744:Pyrimidinones / Q000737:chemistry / Q000494:pharmacology*; D011869:Radioligand Assay; D011966:Receptors, LHRH / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000235:genetics; D017386:Sequence Homology, Amino Acid; D013329:Structure-Activity Relationship; D013941:Thymine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology
chemical_list: C498569:3-(2-amino-2-phenylethyl)-1-(2,6-difluorobenzyl)-5-(2-fluoro-3-methoxyphenyl)-6-methylpyrimidin-2,4-dione; C470760:5-(N-benzyl-N-methylaminomethyl)-1--(2,6-difluorobenzyl)-6-(4-(3-methoxyureido)phenyl)-3-phenylthieno(2,3-d)pyrimidine-2,4(1H,3H)-dione; D007211:Indoles; D008024:Ligands; D010455:Peptides; D010671:Phenylurea Compounds; D011744:Pyrimidinones; D011966:Receptors, LHRH; D013941:Thymine