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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
10
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pubmed:dateCreated |
2010-3-10
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pubmed:abstractText |
Alpha-conotoxins are tightly folded miniproteins that antagonize nicotinic acetylcholine receptors (nAChR) with high specificity for diverse subtypes. Here we report the use of selenocysteine in a supported phase method to direct native folding and produce alpha-conotoxins efficiently with improved biophysical properties. By replacing complementary cysteine pairs with selenocysteine pairs on an amphiphilic resin, we were able to chemically direct all five structural subclasses of alpha-conotoxins exclusively into their native folds. X-ray analysis at 1.4 A resolution of alpha-selenoconotoxin PnIA confirmed the isosteric character of the diselenide bond and the integrity of the alpha-conotoxin fold. The alpha-selenoconotoxins exhibited similar or improved potency at rat diaphragm muscle and alpha3beta4, alpha7, and alpha1beta1 deltagamma nAChRs expressed in Xenopus oocytes plus improved disulfide bond scrambling stability in plasma. Together, these results underpin the development of more stable and potent nicotinic antagonists suitable for new drug therapies, and highlight the application of selenocysteine technology more broadly to disulfide-bonded peptides and proteins.
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
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pubmed:status |
MEDLINE
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pubmed:month |
Mar
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pubmed:issn |
1520-5126
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pubmed:author |
pubmed-author:AdamsDavid JDJ,
pubmed-author:AlewoodPaul FPF,
pubmed-author:ArmishawChristopher JCJ,
pubmed-author:ChoyPeng TPT,
pubmed-author:CraikDavid JDJ,
pubmed-author:DalyNorelle LNL,
pubmed-author:GrishinAnton AAA,
pubmed-author:HuShu-HongSH,
pubmed-author:LewisRichard JRJ,
pubmed-author:MartinJennifer LJL,
pubmed-author:MuttenthalerMarkusM,
pubmed-author:NevinSimon TST,
pubmed-author:NgoShyuan TST,
pubmed-author:NoakesPeter GPG,
pubmed-author:WangChing-I ACI
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pubmed:issnType |
Electronic
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pubmed:day |
17
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pubmed:volume |
132
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
3514-22
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pubmed:meshHeading |
pubmed-meshheading:20163143-Amino Acid Sequence,
pubmed-meshheading:20163143-Animals,
pubmed-meshheading:20163143-Conotoxins,
pubmed-meshheading:20163143-Crystallography, X-Ray,
pubmed-meshheading:20163143-Diaphragm,
pubmed-meshheading:20163143-Models, Molecular,
pubmed-meshheading:20163143-Molecular Sequence Data,
pubmed-meshheading:20163143-Muscle Contraction,
pubmed-meshheading:20163143-Nicotinic Antagonists,
pubmed-meshheading:20163143-Oocytes,
pubmed-meshheading:20163143-Protein Folding,
pubmed-meshheading:20163143-Protein Stability,
pubmed-meshheading:20163143-Rats,
pubmed-meshheading:20163143-Receptors, Nicotinic,
pubmed-meshheading:20163143-Resins, Synthetic,
pubmed-meshheading:20163143-Selenocysteine,
pubmed-meshheading:20163143-Structure-Activity Relationship,
pubmed-meshheading:20163143-Xenopus
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pubmed:year |
2010
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pubmed:articleTitle |
Solving the alpha-conotoxin folding problem: efficient selenium-directed on-resin generation of more potent and stable nicotinic acetylcholine receptor antagonists.
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pubmed:affiliation |
Institute for Molecular Bioscience, Division of Chemistry and Structural Biology, The University of Queensland, Brisbane, Queensland 4072, Australia.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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