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Article: Latent specificity of molecular recognition in sodium channels engineered to discriminate between two "indistinguishable" μ-Conotoxins

TitleLatent specificity of molecular recognition in sodium channels engineered to discriminate between two "indistinguishable" μ-Conotoxins
Authors
KeywordsChemicals And Cas Registry Numbers
Issue Date2001
PublisherAmerican Chemical Society. The Journal's web site is located at http://pubs.acs.org/biochemistry
Citation
Biochemistry, 2001, v. 40 n. 20, p. 6002-6008 How to Cite?
Abstractμ-Conotoxins (μ-CTX) are potent oligopeptide blockers of sodium channels. The best characterized forms of μ-CTX, GIIIA and GIIIB, have similar primary and three-dimensional structures and comparable potencies (IC50 ∼30 nM) for block of wild-type skeletal muscle Na+ channels. The two toxins are thus considered to be indistinguishable by their target channels. We have found mutations in the domain II pore region (D762K and E765K) that decrease GIIIB blocking affinity ∼200-fold, but reduce GIIIA affinity by only ∼4-fold, compared with wild-type channels. Synthetic μ-CTX GIIIA mutants reveal that the critical residue for differential recognition is at position 14, the site of the only charge difference between the two toxin isoforms. Therefore, engineered Na+ channels, but not wild-type channels, can discriminate between two highly homologous conotoxins. Latent specificity of toxin - Channel interactions, such as that revealed here, is a principle worthy of exploitation in the design and construction of improved biosensors.
Persistent Identifierhttp://hdl.handle.net/10722/91637
ISSN
2015 Impact Factor: 2.876
2015 SCImago Journal Rankings: 1.769
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorLi, RAen_HK
dc.contributor.authorEnnis, ILen_HK
dc.contributor.authorTomaselli, GFen_HK
dc.contributor.authorFrench, RJen_HK
dc.contributor.authorMarbán, Een_HK
dc.date.accessioned2010-09-17T10:22:35Z-
dc.date.available2010-09-17T10:22:35Z-
dc.date.issued2001en_HK
dc.identifier.citationBiochemistry, 2001, v. 40 n. 20, p. 6002-6008en_HK
dc.identifier.issn0006-2960en_HK
dc.identifier.urihttp://hdl.handle.net/10722/91637-
dc.description.abstractμ-Conotoxins (μ-CTX) are potent oligopeptide blockers of sodium channels. The best characterized forms of μ-CTX, GIIIA and GIIIB, have similar primary and three-dimensional structures and comparable potencies (IC50 ∼30 nM) for block of wild-type skeletal muscle Na+ channels. The two toxins are thus considered to be indistinguishable by their target channels. We have found mutations in the domain II pore region (D762K and E765K) that decrease GIIIB blocking affinity ∼200-fold, but reduce GIIIA affinity by only ∼4-fold, compared with wild-type channels. Synthetic μ-CTX GIIIA mutants reveal that the critical residue for differential recognition is at position 14, the site of the only charge difference between the two toxin isoforms. Therefore, engineered Na+ channels, but not wild-type channels, can discriminate between two highly homologous conotoxins. Latent specificity of toxin - Channel interactions, such as that revealed here, is a principle worthy of exploitation in the design and construction of improved biosensors.en_HK
dc.languageengen_HK
dc.publisherAmerican Chemical Society. The Journal's web site is located at http://pubs.acs.org/biochemistryen_HK
dc.relation.ispartofBiochemistryen_HK
dc.subjectChemicals And Cas Registry Numbersen_HK
dc.subject.meshAmino Acid Sequenceen_HK
dc.subject.meshAmino Acid Substitution - geneticsen_HK
dc.subject.meshAnimalsen_HK
dc.subject.meshArginine - geneticsen_HK
dc.subject.meshAspartic Acid - geneticsen_HK
dc.subject.meshConotoxins - biosynthesis - genetics - metabolism - pharmacologyen_HK
dc.subject.meshGlutamic Acid - geneticsen_HK
dc.subject.meshGlutamine - geneticsen_HK
dc.subject.meshLysine - geneticsen_HK
dc.subject.meshMembrane Potentials - drug effects - geneticsen_HK
dc.subject.meshMolecular Sequence Dataen_HK
dc.subject.meshMollusk Venoms - biosynthesis - genetics - metabolism - pharmacologyen_HK
dc.subject.meshMutagenesis, Site-Directeden_HK
dc.subject.meshPatch-Clamp Techniquesen_HK
dc.subject.meshProtein Binding - geneticsen_HK
dc.subject.meshRatsen_HK
dc.subject.meshSodium Channel Blockersen_HK
dc.subject.meshSodium Channels - biosynthesis - genetics - metabolismen_HK
dc.subject.meshThermodynamicsen_HK
dc.titleLatent specificity of molecular recognition in sodium channels engineered to discriminate between two "indistinguishable" μ-Conotoxinsen_HK
dc.typeArticleen_HK
dc.identifier.emailLi, RA:ronaldli@hkucc.hku.hken_HK
dc.identifier.authorityLi, RA=rp01352en_HK
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1021/bi010077fen_HK
dc.identifier.pmid11352735en_HK
dc.identifier.scopuseid_2-s2.0-0035918530en_HK
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-0035918530&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume40en_HK
dc.identifier.issue20en_HK
dc.identifier.spage6002en_HK
dc.identifier.epage6008en_HK
dc.identifier.isiWOS:000168932900017-
dc.publisher.placeUnited Statesen_HK
dc.identifier.scopusauthoridLi, RA=7404724466en_HK
dc.identifier.scopusauthoridEnnis, IL=6604033332en_HK
dc.identifier.scopusauthoridTomaselli, GF=7005223451en_HK
dc.identifier.scopusauthoridFrench, RJ=7202789440en_HK
dc.identifier.scopusauthoridMarbán, E=8075977300en_HK

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