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bioRxiv · 10.1101/2022.08.22.504816

Stereoretentive Post-Translational Protein Editing

Fu, X.·Yuan, Y.·Jha, A.·Levin, N.·Giltrap, A. M.·Ren, J.·Mamalis, D.·Mohammed, S.·Davis, B. G.
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Abstract

Chemical post-translational methods now allow convergent side-chain editing of proteins as a form of direct chemical mutagenesis without needing to resort to genetic intervention. Current approaches that allow the creation of constitutionally native side-chains via C-C formation using off-protein carbon-centred C* radicals added to unnatural amino acid radical acceptor SOMOphile tags such as dehydroalanine are benign and wide-ranging. However, they also typically create epimeric mixtures of D-/L-residues. Here we describe a light-mediated desulfurative method that, through the creation and reaction of stereoretained on-protein L-alanyl C{beta}* radicals, allows C{beta}-H{gamma}, C{beta}-O{gamma}, C{beta}-Se{gamma}, C{beta}-B{gamma} and C{beta}-C{gamma} bond formation to flexibly generate site-selectively edited proteins with full retention of native stereochemistry under mild conditions from a natural amino acid. This methodology shows great potential to explore protein side-chain diversity and construct useful bioconjugates. Table of Contents Image O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=32 SRC="FIGDIR/small/504816v1_ufig1.gif" ALT="Figure 1"> View larger version (7K): org.highwire.dtl.DTLVardef@1ccd60corg.highwire.dtl.DTLVardef@f8ca72org.highwire.dtl.DTLVardef@1b33835org.highwire.dtl.DTLVardef@12f32e9_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Fu, X., Yuan, Y., Jha, A., Levin, N., Giltrap, A. M., Ren, J., Mamalis, D., Mohammed, S., Davis, B. G.. 2022-08-23. Stereoretentive Post-Translational Protein Editing. https://doi.org/10.1101/2022.08.22.504816

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