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Article: Charge conversion enables quantification of the proximity between a normally-neutral μ-conotoxin (GIIIA) site and the Na+ channel pore

TitleCharge conversion enables quantification of the proximity between a normally-neutral μ-conotoxin (GIIIA) site and the Na+ channel pore
Authors
KeywordsChemicals And Cas Registry Numbers
Issue Date2002
PublisherElsevier BV. The Journal's web site is located at http://www.elsevier.com/locate/febslet
Citation
Febs Letters, 2002, v. 511 n. 1-3, p. 159-164 How to Cite?
Abstractμ-Conotoxin (μ-CTX) inhibits Na+ flux by obstructing the Na+ channel pore. Previous studies of μ-CTX have focused only on charged toxin residues, ignoring the neutral sites. Here we investigated the proximity between the C-terminal neutral alanine (A22) of μ-CTX and the Na+ channel pore by replacing it with the negatively charged glutamate. The analog A22E and wild-type (WT) μ-CTX exhibited identical nuclear magnetic resonance spectra except at the site of replacement, verifying that they have identical backbone structures. A22E significantly reduced μ-CTX affinity for WT μ1 Na+ channels (90-fold↓), as if the inserted glutamate repels the anionic pore receptor. We then looked for the interacting partner(s) of residue 22 by determining the potency of block of Y401K, Y401A, E758Q, D762K, D762A, E765K, E765A and D1241K channels by WT μ-CTX and A22E, followed by mutant cycle analysis to assess their individual couplings. Our results show that A22E interacts strongly with E765K from domain II (DII) (ΔΔG=2.2±0.1 vs. <1 kcal/mol for others). We conclude that μ-CTX residue 22 closely associates with the DII pore in the toxin-bound channel complex. The approach taken may be further exploited to study the proximity of other neutral toxin residues with the Na+ channel pore. © 2002 Federation of European Biochemical Societies. Published by Elsevier Science B.V. All rights reserved.
Persistent Identifierhttp://hdl.handle.net/10722/91550
ISSN
2015 Impact Factor: 3.519
2015 SCImago Journal Rankings: 2.026
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorLi, RAen_HK
dc.contributor.authorSato, Ken_HK
dc.contributor.authorKodama, Ken_HK
dc.contributor.authorKohno, Ten_HK
dc.contributor.authorXue, Ten_HK
dc.contributor.authorTomaselli, GFen_HK
dc.contributor.authorMarbán, Een_HK
dc.date.accessioned2010-09-17T10:21:13Z-
dc.date.available2010-09-17T10:21:13Z-
dc.date.issued2002en_HK
dc.identifier.citationFebs Letters, 2002, v. 511 n. 1-3, p. 159-164en_HK
dc.identifier.issn0014-5793en_HK
dc.identifier.urihttp://hdl.handle.net/10722/91550-
dc.description.abstractμ-Conotoxin (μ-CTX) inhibits Na+ flux by obstructing the Na+ channel pore. Previous studies of μ-CTX have focused only on charged toxin residues, ignoring the neutral sites. Here we investigated the proximity between the C-terminal neutral alanine (A22) of μ-CTX and the Na+ channel pore by replacing it with the negatively charged glutamate. The analog A22E and wild-type (WT) μ-CTX exhibited identical nuclear magnetic resonance spectra except at the site of replacement, verifying that they have identical backbone structures. A22E significantly reduced μ-CTX affinity for WT μ1 Na+ channels (90-fold↓), as if the inserted glutamate repels the anionic pore receptor. We then looked for the interacting partner(s) of residue 22 by determining the potency of block of Y401K, Y401A, E758Q, D762K, D762A, E765K, E765A and D1241K channels by WT μ-CTX and A22E, followed by mutant cycle analysis to assess their individual couplings. Our results show that A22E interacts strongly with E765K from domain II (DII) (ΔΔG=2.2±0.1 vs. <1 kcal/mol for others). We conclude that μ-CTX residue 22 closely associates with the DII pore in the toxin-bound channel complex. The approach taken may be further exploited to study the proximity of other neutral toxin residues with the Na+ channel pore. © 2002 Federation of European Biochemical Societies. Published by Elsevier Science B.V. All rights reserved.en_HK
dc.languageengen_HK
dc.publisherElsevier BV. The Journal's web site is located at http://www.elsevier.com/locate/febsleten_HK
dc.relation.ispartofFEBS Lettersen_HK
dc.subjectChemicals And Cas Registry Numbersen_HK
dc.subject.meshAlanine - genetics - metabolismen_HK
dc.subject.meshAmino Acid Substitution - geneticsen_HK
dc.subject.meshAnimalsen_HK
dc.subject.meshBinding Sitesen_HK
dc.subject.meshConotoxins - chemistry - genetics - metabolismen_HK
dc.subject.meshElectrophysiologyen_HK
dc.subject.meshGlutamic Acid - genetics - metabolismen_HK
dc.subject.meshKineticsen_HK
dc.subject.meshModels, Molecularen_HK
dc.subject.meshMuscle, Skeletal - metabolismen_HK
dc.subject.meshMutagenesis, Site-Directed - geneticsen_HK
dc.subject.meshNuclear Magnetic Resonance, Biomolecularen_HK
dc.subject.meshPatch-Clamp Techniquesen_HK
dc.subject.meshProtein Bindingen_HK
dc.subject.meshProtein Conformationen_HK
dc.subject.meshRatsen_HK
dc.subject.meshSodium Channel Blockersen_HK
dc.subject.meshSodium Channels - chemistry - genetics - metabolismen_HK
dc.subject.meshStatic Electricityen_HK
dc.titleCharge conversion enables quantification of the proximity between a normally-neutral μ-conotoxin (GIIIA) site and the Na+ channel poreen_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.doi10.1016/S0014-5793(01)03316-6en_HK
dc.identifier.pmid11821068-
dc.identifier.scopuseid_2-s2.0-0037196391en_HK
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-0037196391&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume511en_HK
dc.identifier.issue1-3en_HK
dc.identifier.spage159en_HK
dc.identifier.epage164en_HK
dc.identifier.isiWOS:000173628000031-
dc.publisher.placeNetherlandsen_HK
dc.identifier.scopusauthoridLi, RA=7404724466en_HK
dc.identifier.scopusauthoridSato, K=7406409211en_HK
dc.identifier.scopusauthoridKodama, K=7401760033en_HK
dc.identifier.scopusauthoridKohno, T=7201820312en_HK
dc.identifier.scopusauthoridXue, T=7005064190en_HK
dc.identifier.scopusauthoridTomaselli, GF=7005223451en_HK
dc.identifier.scopusauthoridMarbán, E=8075977300en_HK

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