Solution structure of mu-conotoxin PIIIA, a preferential inhibitor of persistent tetrodotoxin-sensitive sodium channels

Nielsen, Katherine J., Watson, Michael, Adams, David J., Hammarstrom, Anna K., Gage, Peter W., Hill, Justine M., Craik, David J., Thomas, Linda, Adams, Denise, Alewood, Paul F., and Lewis, Richard J. (2002) Solution structure of mu-conotoxin PIIIA, a preferential inhibitor of persistent tetrodotoxin-sensitive sodium channels. Journal of Biological Chemistry, 277 (30). pp. 27247-27255.

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Mu-conotoxins are peptide inhibitors of voltage-sensitive sodium channels (VSSCs). Synthetic forms of mu-conotoxins PIIIA and PIIIA-(2-22) were found to inhibit tetrodotoxin (TTX)-sensitive VSSC current but had little effect on TTX-resistant VSSC current in sensory ganglion neurons. In rat brain neurons, these peptides preferentially inhibited the persistent over the transient VSSC current. Radioligand binding assays revealed that PIIIA, PIIIA-(2-22), and mu-conotoxins GIIIB discriminated among TTX-sensitive VSSCs in rat brain, that these and GIIIC discriminated among the corresponding VSSCs in human brain, and GIIIA had low affinity for neuronal VSSCs. (1)H NMR studies found that PIIIA adopts two conformations in solution due to cis/trans isomerization at hydroxyproline 8. The major trans conformation results in a three-dimensional structure that is significantly different from the previously identified conformation of mu-conotoxins GIIIA and GIIIB that selectively target TTX-sensitive muscle VSSCs. Comparison of the structures and activity of PIIIA to muscle-selective mu-conotoxins provides an insight into the structural requirements for inhibition of different TTX-sensitive sodium channels by mu-conotoxins

Item ID: 266
Item Type: Article (Research - C1)
ISSN: 1083-351X
Keywords: amino acid sequence, animals, brain/drug effects/metabolism, conotoxins/*chemistry, dose-response relationship, drug electrophysiology, hippocampus/metabolism, Humans, inhibitory concentration 50, magnetic resonance spectroscopy, models, molecular, molecular sequence data muscle, skeletal/drug effects/metabolism, neurons/metabolism peptide biosynthesis, protein conformation, radioligand assay, rats, sodium channels/*chemistry, tetrodotoxin/*pharmacology
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© 2002 Journal of Biological Chemistry, American Society for Biochemistry and Molecular Biology, Inc., Bethesda, MD, 20814. Reproduced with permission from American Society for Biochemistry and Molecular Biology.

Date Deposited: 08 Sep 2006
FoR Codes: 03 CHEMICAL SCIENCES > 0306 Physical Chemistry (incl Structural) > 030606 Structural Chemistry and Spectroscopy @ 50%
06 BIOLOGICAL SCIENCES > 0601 Biochemistry and Cell Biology @ 50%
SEO Codes: 97 EXPANDING KNOWLEDGE > 970106 Expanding Knowledge in the Biological Sciences @ 50%
97 EXPANDING KNOWLEDGE > 970103 Expanding Knowledge in the Chemical Sciences @ 50%
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