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J. Biol. Chem., Vol. 282, Issue 24, 17921-17929, June 15, 2007

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Structural Determinants for Ligand-Receptor Conformational Selection in a Peptide G Protein-coupled Receptor^*

Zhi-Liang Lu¹, Marla Coetsee, Colin D. White, and Robert P. Millar

From the Medical Research Council Human Reproductive Sciences Unit, Centre for Reproductive Biology, The Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, Scotland, United Kingdom and The University of Cape Town, Cape Town 7925, South Africa

G protein coupled receptors (GPCRs) modulate the majority of physiological processes through specific intermolecular interactions with structurally diverse ligands and activation of differential intracellular signaling. A key issue yet to be resolved is how GPCRs developed selectivity and diversity of ligand binding and intracellular signaling 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 Asn^7.45 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 modeling and site-directed mutagenesis, we demonstrated that the highly conserved Asn^7.45 makes intramolecular interactions with a highly conserved Cys^6.47 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 signaling efficacy. These results reveal GnRH ligand and receptor structural elements for conformational selection, and support co-evolution of GnRH ligand and receptor conformations.

Received for publication, November 8, 2006 , and in revised form, April 18, 2007.

^* This work was supported by the Medical Research Council, United Kingdom (to Z. L. L., M. C., C. D. W., and R. P. M.) and the Medical Research Council of South Africa, Commonwealth Scholarship and Ardana (to M. C.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: The Medical Research Council Human Reproductive Sciences Unit, The Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, Scotland, UK. Tel.: 44-131-242-6218; Fax: 44-131-242-6231; E-mail: z.lu{at}hrsu.mrc.ac.uk.

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