Asn 102 of the Gonadotropin-releasing Hormone Receptor Is a Critical Determinant of Potency for Agonists Containing C-terminal Glycinamide

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dc.contributor.authorDavidson, James S
dc.contributor.authorMcArdle, Craig A
dc.contributor.authorDavies, Peter
dc.contributor.authorElario, Ricardo
dc.contributor.authorFlanagan, Colleen A
dc.contributor.authorMillar, Robert P
dc.date.accessioned2021-10-08T07:20:44Z
dc.date.available2021-10-08T07:20:44Z
dc.date.issued1996
dc.description.abstractWe demonstrate a critical role for Asn102 of the human gonadotropin-releasing hormone (GnRH) receptor in the binding of GnRH. Mutation of Asn102, located at the top of the second transmembrane helix, to Ala resulted in a 225-fold loss of potency for GnRH. Eight GnRH analogs, all containing glycinamide C termini like GnRH, showed similar losses of potency between 95- and 750-fold for the [Ala102]GnRHR, compared with wild-type receptor. In contrast, four GnRH analogs that had ethylamide in place of the C-terminal glycinamide residue, showed much smaller decreases in potency between 2.4- and 11-fold. In comparisons of three agonist pairs, differing only at the C terminus, glycinamide derivatives showed an 11-20-fold greater loss of potency for the mutant receptor than their respective ethylamide derivatives. Thus Asn102 is a critical determinant of potency specifically for ligands with C-terminal glycinamide, while ligands with C-terminal ethylamide are less dependent on Asn102. These findings indicate a role for Asn102 in the docking of the glycinamide C terminus and are consistent with hydrogen bonding of the Asn102 side chain with the C-terminal amide moiety. Taken with previous data, they suggest a region of the GnRH receptor formed by the top of helices 2 and 7 as a binding pocket for the C-terminal part of the ligand.
dc.identifier.apacitationDavidson, J. S., McArdle, C. A., Davies, P., Elario, R., Flanagan, C. A., & Millar, R. P. (1996). Asn 102 of the Gonadotropin-releasing Hormone Receptor Is a Critical Determinant of Potency for Agonists Containing C-terminal Glycinamide. <i>The Journal of Biological Chemistry</i>, 271(26), 15510 - 15514. http://hdl.handle.net/11427/34994en_ZA
dc.identifier.chicagocitationDavidson, James S, Craig A McArdle, Peter Davies, Ricardo Elario, Colleen A Flanagan, and Robert P Millar "Asn 102 of the Gonadotropin-releasing Hormone Receptor Is a Critical Determinant of Potency for Agonists Containing C-terminal Glycinamide." <i>The Journal of Biological Chemistry</i> 271, 26. (1996): 15510 - 15514. http://hdl.handle.net/11427/34994en_ZA
dc.identifier.citationDavidson, J.S., McArdle, C.A., Davies, P., Elario, R., Flanagan, C.A. & Millar, R.P. 1996. Asn 102 of the Gonadotropin-releasing Hormone Receptor Is a Critical Determinant of Potency for Agonists Containing C-terminal Glycinamide. <i>The Journal of Biological Chemistry.</i> 271(26):15510 - 15514. http://hdl.handle.net/11427/34994en_ZA
dc.identifier.issn0021-9258
dc.identifier.issn1083-351X
dc.identifier.ris TY - Journal Article AU - Davidson, James S AU - McArdle, Craig A AU - Davies, Peter AU - Elario, Ricardo AU - Flanagan, Colleen A AU - Millar, Robert P AB - We demonstrate a critical role for Asn102 of the human gonadotropin-releasing hormone (GnRH) receptor in the binding of GnRH. Mutation of Asn102, located at the top of the second transmembrane helix, to Ala resulted in a 225-fold loss of potency for GnRH. Eight GnRH analogs, all containing glycinamide C termini like GnRH, showed similar losses of potency between 95- and 750-fold for the [Ala102]GnRHR, compared with wild-type receptor. In contrast, four GnRH analogs that had ethylamide in place of the C-terminal glycinamide residue, showed much smaller decreases in potency between 2.4- and 11-fold. In comparisons of three agonist pairs, differing only at the C terminus, glycinamide derivatives showed an 11-20-fold greater loss of potency for the mutant receptor than their respective ethylamide derivatives. Thus Asn102 is a critical determinant of potency specifically for ligands with C-terminal glycinamide, while ligands with C-terminal ethylamide are less dependent on Asn102. These findings indicate a role for Asn102 in the docking of the glycinamide C terminus and are consistent with hydrogen bonding of the Asn102 side chain with the C-terminal amide moiety. Taken with previous data, they suggest a region of the GnRH receptor formed by the top of helices 2 and 7 as a binding pocket for the C-terminal part of the ligand. DA - 1996 DB - OpenUCT DP - University of Cape Town IS - 26 J1 - The Journal of Biological Chemistry LK - https://open.uct.ac.za PY - 1996 SM - 0021-9258 SM - 1083-351X T1 - Asn 102 of the Gonadotropin-releasing Hormone Receptor Is a Critical Determinant of Potency for Agonists Containing C-terminal Glycinamide TI - Asn 102 of the Gonadotropin-releasing Hormone Receptor Is a Critical Determinant of Potency for Agonists Containing C-terminal Glycinamide UR - http://hdl.handle.net/11427/34994 ER - en_ZA
dc.identifier.urihttp://hdl.handle.net/11427/34994
dc.identifier.vancouvercitationDavidson JS, McArdle CA, Davies P, Elario R, Flanagan CA, Millar RP. Asn 102 of the Gonadotropin-releasing Hormone Receptor Is a Critical Determinant of Potency for Agonists Containing C-terminal Glycinamide. The Journal of Biological Chemistry. 1996;271(26):15510 - 15514. http://hdl.handle.net/11427/34994.en_ZA
dc.language.isoeng
dc.publisher.departmentDivision of Chemical Pathology
dc.publisher.facultyFaculty of Health Sciences
dc.sourceThe Journal of Biological Chemistry
dc.source.journalissue26
dc.source.journalvolume271
dc.source.pagination15510 - 15514
dc.source.urihttps://dx.doi.org/10.1074/jbc.271.26.15510
dc.subject.otherAmino Acid Sequence
dc.subject.otherAsparagine
dc.subject.otherBinding Sites
dc.subject.otherGlycine
dc.subject.otherGonadotropin-Releasing Hormone
dc.subject.otherHumans
dc.subject.otherInositol Phosphates
dc.subject.otherLigands
dc.subject.otherMolecular Sequence Data
dc.subject.otherMutagenesis, Site-Directed
dc.subject.otherOligodeoxyribonucleotides
dc.subject.otherProtein Binding
dc.subject.otherProtein Structure, Tertiary
dc.subject.otherReceptors, LHRH
dc.subject.otherSignal Transduction
dc.subject.otherStructure-Activity Relationship
dc.titleAsn 102 of the Gonadotropin-releasing Hormone Receptor Is a Critical Determinant of Potency for Agonists Containing C-terminal Glycinamide
dc.typeJournal Article
uct.type.publicationResearch
uct.type.resourceJournal Article
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