Cloning, synthesis, and characterization of αO-conotoxin GeXIVA, a potent α9α10 nicotinic acetylcholine receptor antagonist

Luo, Sulan, Zhangsun, Dongting, Harvey, Peta J., Kaas, Quentin, Wu, Yong, Zhu, Xiaopeng, Hu, Yuanyan, Li, Xiaodan, Tsetlin, Victor. I., Christensen, Sean, Romero, Haylie K., McIntrye, Melissa, Dowell, Cheryl, Baxter, James, C., Elmslie, Keith S., Craik, David J. and McIntosh, Michael (2015) Cloning, synthesis, and characterization of αO-conotoxin GeXIVA, a potent α9α10 nicotinic acetylcholine receptor antagonist. PNAS: Proceedings of the National Academy of Sciences of the United States of America, 112 30: e4026-e4035. doi:10.1073/pnas.1503617112


Author Luo, Sulan
Zhangsun, Dongting
Harvey, Peta J.
Kaas, Quentin
Wu, Yong
Zhu, Xiaopeng
Hu, Yuanyan
Li, Xiaodan
Tsetlin, Victor. I.
Christensen, Sean
Romero, Haylie K.
McIntrye, Melissa
Dowell, Cheryl
Baxter, James, C.
Elmslie, Keith S.
Craik, David J.
McIntosh, Michael
Title Cloning, synthesis, and characterization of αO-conotoxin GeXIVA, a potent α9α10 nicotinic acetylcholine receptor antagonist
Journal name PNAS: Proceedings of the National Academy of Sciences of the United States of America   Check publisher's open access policy
ISSN 0027-8424
1091-6490
Publication date 2015-07-28
Sub-type Article (original research)
DOI 10.1073/pnas.1503617112
Open Access Status Not yet assessed
Volume 112
Issue 30
Start page e4026
End page e4035
Total pages 10
Place of publication Washington, DC United States
Publisher National Academy of Sciences
Collection year 2016
Language eng
Formatted abstract
We identified a previously unidentified conotoxin gene from Conus generalis whose precursor signal sequence has high similarity to the O1-gene conotoxin superfamily. The predicted mature peptide, αO-conotoxin GeXIVA (GeXIVA), has four Cys residues, and its three disulfide isomers were synthesized. Previously pharmacologically characterized O1-superfamily peptides, exemplified by the US Food and Drug Administration-approved pain medication, ziconotide, contain six Cys residues and are calcium, sodium, or potassium channel antagonists. However, GeXIVA did not inhibit calcium channels but antagonized nicotinic AChRs (nAChRs), most potently on the α9α10 nAChR subtype (IC50 = 4.6 nM). Toxin blockade was voltage-dependent, and kinetic analysis of toxin dissociation indicated that the binding site of GeXIVA does not overlap with the binding site of the competitive antagonist α-conotoxin RgIA. Surprisingly, the most active disulfide isomer of GeXIVA is the bead isomer, comprising, according to NMR analysis, two well-resolved but uncoupled disulfide-restrained loops. The ribbon isomer is almost as potent but has a more rigid structure built around a short 310-helix. In contrast to most α-conotoxins, the globular isomer is the least potent and has a flexible, multiconformational nature. GeXIVA reduced mechanical hyperalgesia in the rat chronic constriction injury model of neuropathic pain but had no effect on motor performance, warranting its further investigation as a possible therapeutic agent.
Keyword αO-conotoxin GeXIVA
α9α10 nAChR
Nicotinic
NMR
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2016 Collection
Institute for Molecular Bioscience - Publications
 
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Created: Fri, 07 Aug 2015, 23:43:07 EST by Susan Allen on behalf of Institute for Molecular Bioscience