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dc.contributor.authorO'Brien, Margaret
dc.contributor.authorSmith, Terry
dc.date.accessioned2014-10-22T12:16:47Z
dc.date.available2014-10-22T12:16:47Z
dc.date.issued2013-10-23
dc.identifier.citationKoehbach, J,O'Brien, M,Muttenthaler, M,Miazzo, M,Akcan, M,Elliott, AG,Daly, NL,Harvey, PJ,Arrowsmith, S,Gunasekera, S,Smith, TJ,Wray, S,Goransson, U,Dawson, PE,Craik, DJ,Freissmuth, M,Gruber, CW (2013) 'Oxytocic plant cyclotides as templates for peptide G protein-coupled receptor ligand design'. Proceedings Of The National Academy Of Sciences Of The United States Of America, 110 (52):21183-21188.en_US
dc.identifier.urihttp://hdl.handle.net/10379/4667
dc.descriptionJournal articleen_US
dc.description.abstractCyclotides are plant peptides comprising a circular backbone and three conserved disulfide bonds that confer them with exceptional stability. They were originally discovered in Oldenlandia affinis based on their use in traditional African medicine to accelerate labor. Recently, cyclotides have been identified in numerous plant species of the coffee, violet, cucurbit, pea, potato, and grass families. Their unique structural topology, high stability, and tolerance to sequence variation make them promising templates for the development of peptide-based pharmaceuticals. However, the mechanisms underlying their biological activities remain largely unknown; specifically, a receptor for a native cyclotide has not been reported hitherto. Using bioactivity-guided fractionation of an herbal peptide extract known to indigenous healers as "kalata-kalata," the cyclotide kalata B7 was found to induce strong contractility on human uterine smooth muscle cells. Radioligand displacement and second messenger-based reporter assays confirmed the oxytocin and vasopressin V-1a receptors, members of the G protein-coupled receptor family, as molecular targets for this cyclotide. Furthermore, we show that cyclotides can serve as templates for the design of selective G protein-coupled receptor ligands by generating an oxytocin-like peptide with nanomolar affinity. This nonapeptide elicited dose-dependent contractions on human myometrium. These observations provide a proof of concept for the development of cyclotide-based peptide ligands.en_US
dc.description.sponsorshipAustrian Science Fund Grant P22889-B11; European Union Seventh Framework Programme (FP7/2007-2013) [Grant Agreement 254897]en_US
dc.formatapplication/pdfen_US
dc.language.isoenen_US
dc.publisherNational Academy Of Sciences Of The United States Of Americaen_US
dc.relation.ispartofProceedings Of The National Academy Of Sciences Of The United States Of Americaen
dc.subjectCircular plant peptideen_US
dc.subjectPeptide ligand designen_US
dc.subjectUterotonicen_US
dc.subjectChemical pharmacologyen_US
dc.subjectPeptide drugsen_US
dc.subjectCyclic cystine knoten_US
dc.subjectKalata B1en_US
dc.subjectUterine contractilityen_US
dc.subjectHuman myometriumen_US
dc.subjectDrug designen_US
dc.subjectVasopressinen_US
dc.subjectAntagonistsen_US
dc.subjectBindingen_US
dc.subjectAgonisten_US
dc.subjectMechanismen_US
dc.titleOxytocic plant cyclotides as templates for peptide G protein-coupled receptor ligand designen_US
dc.typeArticleen_US
dc.date.updated2014-10-21T16:44:02Z
dc.identifier.doiDOI 10.1073/pnas.1311183110
dc.local.publishedsourcehttp://dx.doi.org/10.1073/pnas.1311183110en_US
dc.description.peer-reviewedpeer-reviewed
dc.contributor.funder|~|
dc.internal.rssid5733904
dc.local.contactTerry Smith, School Of Natural Sciences, Nui Galway. 2022 Email: terry.smith@nuigalway.ie
dc.local.copyrightcheckedNo
dc.local.versionACCEPTED
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