| Author |
Wu, Yong Christensen, Sean Romero, Haylie K. Baxter, James C. Li, Xiaodan Dowell, Cheryl Zhangsun, Dongting Craik, David J. Tsetlin, Victor I. Luo, Sulan Harvey, Peta J. Zhu, Xiaopeng Kaas, Quentin Hu, Yuanyan Mcintyre, Melissa Mcintosh, J. Michael Elmslie, Keith S. |
| Description |
Author Affiliation: Luo S ( Key Laboratory of Tropical Biological Resources, Ministry of Education, Key Laboratory for Marine Drugs of Haikou, Hainan University, Haikou Hainan 570228, China); Zhangsun D ( Key Laboratory of Tropical Biological Resources, Ministry of Education, Key Laboratory for Marine Drugs of Haikou, Hainan University, Haikou Hainan 570228, China); Harvey PJ ( Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia); Kaas Q ( Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia); Wu Y ( Key Laboratory of Tropical Biological Resources, Ministry of Education, Key Laboratory for Marine Drugs of Haikou, Hainan University, Haikou Hainan 570228, China); Zhu X ( Key Laboratory of Tropical Biological Resources, Ministry of Education, Key Laboratory for Marine Drugs of Haikou, Hainan University, Haikou Hainan 570228, China); Hu Y ( Key Laboratory of Tropical Biological Resources, Ministry of Education, Key Laboratory for Marine Drugs of Haikou, Hainan University, Haikou Hainan 570228, China); Li X ( Key Laboratory of Tropical Biological Resources, Ministry of Education, Key Laboratory for Marine Drugs of Haikou, Hainan University, Haikou Hainan 570228, China); Tsetlin VI ( Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow 117997, Russia); Christensen S ( Department of Biology and Psychiatry, University of Utah, Salt Lake City, UT 84112); Romero HK ( Department of Biology and Psychiatry, University of Utah, Salt Lake City, UT 84112); McIntyre M ( Department of Biology and Psychiatry, University of Utah, Salt Lake City, UT 84112); Dowell C ( Department of Biology and Psychiatry, University of Utah, Salt Lake City, UT 84112); Baxter JC ( Department of Pharmacology, Kirksville College of Osteopathic Medicine, A. T. Still University, Kirksville, MO 63501); Elmslie KS ( Department of Pharmacology, Kirksville College of Osteopathic Medicine, A. T. Still University, Kirksville, MO 63501); Craik DJ ( Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia); McIntosh JM ( Department of Biology and Psychiatry, University of Utah, Salt Lake City, UT 84112); |
| 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, O-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 9 10 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 -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 -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. |
