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Papers In Press, published online ahead of print April 23, 2007
MRC Human Reproductive Sciences Unit, The Queen's Medical Research Institute, Edinburgh EH16 4TJ
Corresponding Author: z.lu{at}hrsu.mrc.ac.uk
G protein coupled receptors (GPCRs) modulate the majority of physiological processes through specific intermolecular interactions with structurally diverse ligands and activation of differential intracellular signalling. A key issue yet to be resolved is how GPCRs developed selectivity and diversity of ligand binding and intracellular signalling during evolution. We have explored the structural basis of selectivity of naturally occurring gonadotropin-releasing hormones (GnRHs) from different species in the single functional human GnRH receptor. We found that the highly variable amino acids in position 8 of the naturally occurring isoforms of GnRH play a discriminating role in selecting receptor conformational states. The human GnRH receptor has a higher affinity for the cognate GnRH I but a lower affinity for GnRH II and GnRHs from other species possessing substitutions for Arg8. The latter were partial agonists in the human GnRH receptor. Mutation of Asn7.45 in transmembrane domain (TM) 7 had no effect on GnRH I affinity but specifically increased affinity for other GnRHs and converted them to full agonists. Using molecular modelling and site-directed mutagenesis, we demonstrated that the highly conserved Asn7.45 makes intramolecular interactions with a highly conserved Cys6.47 in TM 6, suggesting that disruption of this intramolecular interaction induces a receptor conformational change which allosterically alters ligand specific binding sites and changes ligand selectivity and signalling efficacy. These results reveal GnRH ligand and receptor structural elements for conformational selection, and support co-evolution of GnRH ligand and receptor conformations.
J. Biol. Chem, 10.1074/jbc.M610413200
Submitted on November 8, 2006
Revised on April 18, 2007
Accepted on April 23, 2007
Structural determinants for ligand-receptor conformational selection in a peptide G protein-coupled receptor
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