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

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dc.contributor.authorLu, Zhi-Liang
dc.contributor.authorCoetsee, Marla
dc.contributor.authorWhite, Colin D
dc.contributor.authorMillar, Robert P
dc.date.accessioned2021-10-08T07:22:52Z
dc.date.available2021-10-08T07:22:52Z
dc.date.issued2007
dc.description.abstractG 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 Arg(8). 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.
dc.identifier.apacitationLu, Z., Coetsee, M., White, C. D., & Millar, R. P. (2007). Structural Determinants for Ligand-Receptor Conformational Selection in a Peptide G Protein-coupled Receptor. <i>The Journal of Biological Chemistry</i>, 282(24), 17921 - 17929. http://hdl.handle.net/11427/35013en_ZA
dc.identifier.chicagocitationLu, Zhi-Liang, Marla Coetsee, Colin D White, and Robert P Millar "Structural Determinants for Ligand-Receptor Conformational Selection in a Peptide G Protein-coupled Receptor." <i>The Journal of Biological Chemistry</i> 282, 24. (2007): 17921 - 17929. http://hdl.handle.net/11427/35013en_ZA
dc.identifier.citationLu, Z., Coetsee, M., White, C.D. & Millar, R.P. 2007. Structural Determinants for Ligand-Receptor Conformational Selection in a Peptide G Protein-coupled Receptor. <i>The Journal of Biological Chemistry.</i> 282(24):17921 - 17929. http://hdl.handle.net/11427/35013en_ZA
dc.identifier.issn0021-9258
dc.identifier.issn1083-351X
dc.identifier.ris TY - Journal Article AU - Lu, Zhi-Liang AU - Coetsee, Marla AU - White, Colin D AU - Millar, Robert P AB - 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 Arg(8). 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. DA - 2007 DB - OpenUCT DP - University of Cape Town IS - 24 J1 - The Journal of Biological Chemistry LK - https://open.uct.ac.za PY - 2007 SM - 0021-9258 SM - 1083-351X T1 - Structural Determinants for Ligand-Receptor Conformational Selection in a Peptide G Protein-coupled Receptor TI - Structural Determinants for Ligand-Receptor Conformational Selection in a Peptide G Protein-coupled Receptor UR - http://hdl.handle.net/11427/35013 ER - en_ZA
dc.identifier.urihttp://hdl.handle.net/11427/35013
dc.identifier.vancouvercitationLu Z, Coetsee M, White CD, Millar RP. Structural Determinants for Ligand-Receptor Conformational Selection in a Peptide G Protein-coupled Receptor. The Journal of Biological Chemistry. 2007;282(24):17921 - 17929. http://hdl.handle.net/11427/35013.en_ZA
dc.language.isoeng
dc.publisher.departmentDepartment of Medicine
dc.publisher.facultyFaculty of Health Sciences
dc.sourceThe Journal of Biological Chemistry
dc.source.journalissue24
dc.source.journalvolume282
dc.source.pagination17921 - 17929
dc.source.urihttps://dx.doi.org/10.1074/jbc.M610413200
dc.subject.otherAlanine
dc.subject.otherAnimals
dc.subject.otherAsparagine
dc.subject.otherGonadotropin-Releasing Hormone
dc.subject.otherHumans
dc.subject.otherLigands
dc.subject.otherModels, Molecular
dc.subject.otherMutagenesis, Site-Directed
dc.subject.otherProtein Structure, Tertiary
dc.subject.otherReceptors, G-Protein-Coupled
dc.subject.otherReceptors, LHRH
dc.subject.otherLigands
dc.subject.otherReceptors, G-Protein-Coupled
dc.subject.otherReceptors, LHRH
dc.titleStructural Determinants for Ligand-Receptor Conformational Selection in a Peptide G Protein-coupled Receptor
dc.typeJournal Article
uct.type.publicationResearch
uct.type.resourceJournal Article
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