Galan, SRG;
Wickens, JR;
Dadova, J;
Ng, W-L;
Zhang, X;
Simion, RA;
Quinlan, R;
... Davis, BG; + view all
(2018)
Post-translational site-selective protein backbone alpha-deuteration.
Nature Chemical Biology
, 14
(10)
pp. 955-963.
10.1038/s41589-018-0128-y.
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Abstract
Isotopic replacement has long-proven applications in small molecules. However, applications in proteins are largely limited to biosynthetic strategies or exchangeable (for example, N–H/D) labile sites only. The development of postbiosynthetic, C–1H → C–2H/D replacement in proteins could enable probing of mechanisms, among other uses. Here we describe a chemical method for selective protein α-carbon deuteration (proceeding from Cys to dehydroalanine (Dha) to deutero-Cys) allowing overall 1H→2H/D exchange at a nonexchangeable backbone site. It is used here to probe mechanisms of reactions used in protein bioconjugation. This analysis suggests, together with quantum mechanical calculations, stepwise deprotonations via on-protein carbanions and unexpected sulfonium ylides in the conversion of Cys to Dha, consistent with a ‘carba-Swern’ mechanism. The ready application on existing, intact protein constructs (without specialized culture or genetic methods) suggests this C–D labeling strategy as a possible tool in protein mechanism, structure, biotechnology and medicine.
| Type: | Article |
|---|---|
| Title: | Post-translational site-selective protein backbone alpha-deuteration |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1038/s41589-018-0128-y |
| Publisher version: | https://doi.org/10.1038/s41589-018-0128-y |
| Language: | English |
| Additional information: | This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions. |
| Keywords: | Science & Technology, Life Sciences & Biomedicine, Biochemistry & Molecular Biology, NUCLEAR-MAGNETIC-RESONANCE, ELIMINIERUNG BEI SULFONIUMSALZEN, DIHYDROFOLATE-REDUCTASE, CYSTEINE MODIFICATION, DIMETHYL-SULFOXIDE, ZUM MECHANISMUS, DEHYDROALANINE, DEUTERIUM, PEPTIDES, INSIGHTS |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > UCL BEAMS UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences > Dept of Chemistry |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10060853 |
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