AI Article Synopsis
- - Alpha-conotoxins are specialized miniproteins that target nicotinic acetylcholine receptors (nAChR) with precision, and this study explores how to produce them more effectively using selenocysteine.
- - The researchers replaced certain cysteine pairs with selenocysteine pairs on a resin, successfully guiding all five subclasses of alpha-conotoxins into their proper native forms.
- - The resulting alpha-selenoconotoxins showed similar or improved effectiveness against specific nAChRs and enhanced stability for potential use in new drug therapies, demonstrating the versatility of selenocysteine in peptide and protein engineering.
Article Abstract
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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| http://dx.doi.org/10.1021/ja910602h | DOI Listing |
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