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Article: Clockwise Domain Arrangement of the Sodium Channel Revealed by μ-Conotoxin (GIIIA) Docking Orientation

TitleClockwise Domain Arrangement of the Sodium Channel Revealed by μ-Conotoxin (GIIIA) Docking Orientation
Authors
KeywordsChemicals And Cas Registry Numbers
Issue Date2001
PublisherAmerican Society for Biochemistry and Molecular Biology, Inc. The Journal's web site is located at http://www.jbc.org/
Citation
Journal Of Biological Chemistry, 2001, v. 276 n. 14, p. 11072-11077 How to Cite?
Abstractμ-Conotoxins (μ-CTXs) specifically inhibit Na+ flux by occluding the pore of voltage-gated Na+ channels. Although the three-dimensional structures of μ-CTXs are well defined, the molecular configuration of the channel receptor is much less certain; even the fundamental question of whether the four homologous Na+ channel domains are arranged in a clockwise or counter-clockwise configuration remains unanswered. Residues Asp762 and Glu765 from domain II and Asp1241 from domain III of rat skeletal muscle Na+ channels are known to be critical for μ-CTX binding. We probed toxin-channel interactions by determining the potency of block of wild-type, D762K, E765K, and D1241C channels by wild-type and point-mutated μ-CTXs (R1A, Q14D, K11A, K16A, and R19A). Individual interaction energies for different toxin-channel pairs were quantified from the half-blocking concentrations using mutant cycle analysis. We find that Asp762 and Glu765 interact strongly with Gln14 and Arg19 but not Arg1 and that Asp1241 is tightly coupled to Lys16 but not Arg 1 or Lys11. These newly identified toxin-channel interactions within adjacent domains, interpreted in light of the known asymmetric toxin structure, fix the orientation of the toxin with respect to the channel and reveal that the four internal domains of Na+ channels are arranged in a clockwise configuration as viewed from the extracellular surface.
Persistent Identifierhttp://hdl.handle.net/10722/91473
ISSN
2015 Impact Factor: 4.258
2015 SCImago Journal Rankings: 3.151
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorLi, RAen_HK
dc.contributor.authorEnnis, ILen_HK
dc.contributor.authorFrench, RJen_HK
dc.contributor.authorDudley Jr, SCen_HK
dc.contributor.authorTomaselli, GFen_HK
dc.contributor.authorMarbán, Een_HK
dc.date.accessioned2010-09-17T10:19:59Z-
dc.date.available2010-09-17T10:19:59Z-
dc.date.issued2001en_HK
dc.identifier.citationJournal Of Biological Chemistry, 2001, v. 276 n. 14, p. 11072-11077en_HK
dc.identifier.issn0021-9258en_HK
dc.identifier.urihttp://hdl.handle.net/10722/91473-
dc.description.abstractμ-Conotoxins (μ-CTXs) specifically inhibit Na+ flux by occluding the pore of voltage-gated Na+ channels. Although the three-dimensional structures of μ-CTXs are well defined, the molecular configuration of the channel receptor is much less certain; even the fundamental question of whether the four homologous Na+ channel domains are arranged in a clockwise or counter-clockwise configuration remains unanswered. Residues Asp762 and Glu765 from domain II and Asp1241 from domain III of rat skeletal muscle Na+ channels are known to be critical for μ-CTX binding. We probed toxin-channel interactions by determining the potency of block of wild-type, D762K, E765K, and D1241C channels by wild-type and point-mutated μ-CTXs (R1A, Q14D, K11A, K16A, and R19A). Individual interaction energies for different toxin-channel pairs were quantified from the half-blocking concentrations using mutant cycle analysis. We find that Asp762 and Glu765 interact strongly with Gln14 and Arg19 but not Arg1 and that Asp1241 is tightly coupled to Lys16 but not Arg 1 or Lys11. These newly identified toxin-channel interactions within adjacent domains, interpreted in light of the known asymmetric toxin structure, fix the orientation of the toxin with respect to the channel and reveal that the four internal domains of Na+ channels are arranged in a clockwise configuration as viewed from the extracellular surface.en_HK
dc.languageengen_HK
dc.publisherAmerican Society for Biochemistry and Molecular Biology, Inc. The Journal's web site is located at http://www.jbc.org/en_HK
dc.relation.ispartofJournal of Biological Chemistryen_HK
dc.subjectChemicals And Cas Registry Numbersen_HK
dc.subject.meshAnimalsen_HK
dc.subject.meshCell Lineen_HK
dc.subject.meshConotoxinsen_HK
dc.subject.meshPoint Mutationen_HK
dc.subject.meshProtein Conformationen_HK
dc.subject.meshSodium Channels - chemistry - genetics - metabolismen_HK
dc.titleClockwise Domain Arrangement of the Sodium Channel Revealed by μ-Conotoxin (GIIIA) Docking Orientationen_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.doi10.1074/jbc.M010862200en_HK
dc.identifier.pmid11154701-
dc.identifier.scopuseid_2-s2.0-0035815713en_HK
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-0035815713&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume276en_HK
dc.identifier.issue14en_HK
dc.identifier.spage11072en_HK
dc.identifier.epage11077en_HK
dc.identifier.isiWOS:000167980900068-
dc.publisher.placeUnited Statesen_HK
dc.identifier.scopusauthoridLi, RA=7404724466en_HK
dc.identifier.scopusauthoridEnnis, IL=6604033332en_HK
dc.identifier.scopusauthoridFrench, RJ=7202789440en_HK
dc.identifier.scopusauthoridDudley Jr, SC=7006033454en_HK
dc.identifier.scopusauthoridTomaselli, GF=7005223451en_HK
dc.identifier.scopusauthoridMarbán, E=8075977300en_HK

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