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dc.contributor.authorSchroeder, Christina I
dc.contributor.authorEkberg, Jenny
dc.contributor.authorNielsen, Katherine J
dc.contributor.authorAdams, Denise
dc.contributor.authorLoughnan, Marion L
dc.contributor.authorThomas, Linda
dc.contributor.authorAdams, David J
dc.contributor.authorAlewood, Paul F
dc.contributor.authorLewis, Richard J
dc.date.accessioned2017-05-03T16:58:38Z
dc.date.available2017-05-03T16:58:38Z
dc.date.issued2008
dc.date.modified2009-11-25T07:59:58Z
dc.identifier.issn0021-9258
dc.identifier.doi10.1074/jbc.M802852200
dc.identifier.urihttp://hdl.handle.net/10072/26889
dc.description.abstractμ-Conotoxins are small peptide inhibitors of muscle and neuronal tetrodotoxin (TTX)-sensitive voltage-gated sodium channels (VGSCs). Here we report the isolation of μ-conotoxins SIIIA and SIIIB by 125I-TIIIA-guided fractionation of milked Conus striatus venom. SIIIA and SIIIB potently displaced 125I-TIIIA from native rat brain Nav1.2 (IC50 values 10 and 5 nM, respectively) and muscle Nav1.4 (IC50 values 60 and 3 nM, respectively) VGSCs, and both inhibited current through Xenopus oocyte-expressed Nav1.2 and Nav1.4. An alanine scan of SIIIA-(2–20), a pyroglutamate-truncated analogue with enhanced neuronal activity, revealed residues important for affinity and selectivity. Alanine replacement of the solvent-exposed Trp-12, Arg-14, His-16, Arg-18 resulted in large reductions in SIIIA-(2–20) affinity, with His-16 replacement affecting structure. In contrast, [D15A]SIIIA-(2–20) had significantly enhanced neuronal affinity (IC50 0.65 nM), while the double mutant [D15A/H16R]SIIIA-(2–20) showed greatest Nav1.2 versus 1.4 selectivity (136-fold). 1H NMR studies revealed that SIIIA adopted a single conformation in solution comprising a series of turns and anα-helical motif across residues 11–16 that is not found in larger μ-conotoxins. The structure of SIIIA provides a new structural template for the development of neuronally selective inhibitors of TTX-sensitive VGSCs based on the smaller μ-conotoxin pharmacophore.
dc.description.peerreviewedYes
dc.description.publicationstatusYes
dc.languageEnglish
dc.language.isoeng
dc.publisherThe American Society for Biochemistry and Molecular Biology
dc.publisher.placeUnited States of America
dc.publisher.urihttp://www.jbc.org/
dc.relation.ispartofstudentpublicationN
dc.relation.ispartofpagefrom21621
dc.relation.ispartofpageto2128
dc.relation.ispartofissue31
dc.relation.ispartofjournalThe Journal of Biological Chemistry
dc.relation.ispartofvolume283
dc.rights.retentionY
dc.subject.fieldofresearchCell Neurochemistry
dc.subject.fieldofresearchChemical Sciences
dc.subject.fieldofresearchBiological Sciences
dc.subject.fieldofresearchMedical and Health Sciences
dc.subject.fieldofresearchcode060105
dc.subject.fieldofresearchcode03
dc.subject.fieldofresearchcode06
dc.subject.fieldofresearchcode11
dc.titleNeuronally Selective μ-conotoxins From Conus Stiatus Utilize an α-Helical Motif to Mammalian Sodium Channels
dc.typeJournal article
dc.type.descriptionC1 - Articles
dc.type.codeC - Journal Articles
gro.date.issued2008
gro.hasfulltextNo Full Text
gro.griffith.authorEkberg, Jenny A.


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