Antagonist and agonist binding models of the human gonadotropin-releasing hormone receptor

Diversity of actions of GnRHs mediated by ligand-induced selective signaling

“…The use of the rhodopsin crystal structure to comparatively model the GnRH receptor has been extensively validated by our laboratory and independent groups using site-directed mutagenesis and peptide and non-peptide ligand docking [10,53,132]. All known GnRH receptor sequences from a wide range of species were aligned with bovine rhodopsin using "ALIGN2D" within the MODELLER program.…”

G Protein-Coupled Receptor Trafficking in Health and Disease: Lessons Learned to Prepare for Therapeutic Mutant Rescue in Vivo

“…Peptide antagonists occupy GnRHR binding sites that differ from, but that may overlap, the agonist binding pocket, as suggested by mutational analysis and molecular dynamics simulations (Millar et al, 2004;Söderhall et al, 2005). Nevertheless, the fact that agonists, antagonists, and inverse agonists may exhibit distinct selectivities toward the active and the inactive conformation of the receptor suggests that competitive antagonism may occur without any overlap with agonist binding sites (Samama et al, 1993).…”

Histidine7.36(305) in the conserved peptide receptor activation domain of the gonadotropin releasing hormone receptor couples peptide binding and receptor activation

“…7.36(305) (Fersht et al, 1985). On the other hand, three substitutions of (Coetsee et al, 2008;Flanagan et al, 2000;Forfar and Lu, 2011;Soderhall et al, 2005).…”

“…Based on a small number of mutations, many GnRH-receptor models have included contacts of Trp 3 of GnRH agonists with the Trp 6.48 residue (of the CWxPY motif) (Betz et al, 2006b;Chauvin et al, 2000;Chauvin et al, 2001;Hovelmann et al, 2002;Millar et al, 2004;Soderhall et al, 2005 ]-GnRH. Although a π-stacking interaction was proposed (Forfar and Lu, 2011), loss of a weak aromatic interaction is unlikely to account for the large decrease in GnRH binding affinity at the Phe 4.64(178) Ala mutant receptor (Fersht et al, 1985).…”

“…In the absence of crystal structures of the GnRH receptor, computational models have been used to infer ligand binding interactions (Chauvin et al, 2000;Hovelmann et al, 2002;Li et al, 2005;Soderhall et al, 2005). However, only a few of the proposed contacts have been validated with appropriate ligand modifications Sealfon et al, 1997).…”