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

Ronald A. Li, Irene L. Ennis, Gordon F. Tomaselli, Robert J. French, Eduardo Marbán

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

μ-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.

Original languageEnglish (US)
Pages (from-to)6002-6008
Number of pages7
JournalBiochemistry
Volume40
Issue number20
DOIs
StatePublished - May 22 2001
Externally publishedYes

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Conotoxins
Molecular recognition
Sodium Channels
Sodium Channel Blockers
Oligopeptides
Biosensing Techniques
Biosensors
Inhibitory Concentration 50
Muscle
Protein Isoforms
Skeletal Muscle
Mutation

ASJC Scopus subject areas

  • Biochemistry

Cite this

Latent specificity of molecular recognition in sodium channels engineered to discriminate between two "indistinguishable" μ-Conotoxins. / Li, Ronald A.; Ennis, Irene L.; Tomaselli, Gordon F.; French, Robert J.; Marbán, Eduardo.

In: Biochemistry, Vol. 40, No. 20, 22.05.2001, p. 6002-6008.

Research output: Contribution to journalArticle

Li, Ronald A. ; Ennis, Irene L. ; Tomaselli, Gordon F. ; French, Robert J. ; Marbán, Eduardo. / Latent specificity of molecular recognition in sodium channels engineered to discriminate between two "indistinguishable" μ-Conotoxins. In: Biochemistry. 2001 ; Vol. 40, No. 20. pp. 6002-6008.
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