Vanmeert, M;
Razzokov, J;
Mirza, MU;
D Weeks, S;
Schepers, G;
Bogaerts, A;
Rozenski, J;
... Lescrinier, E; + view all
(2019)
Rational design of an XNA ligase through docking of unbound nucleic acids to toroidal proteins.
Nucleic Acids Research
, 47
(13)
pp. 7130-7142.
10.1093/nar/gkz551.
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Abstract
Xenobiotic nucleic acids (XNA) are nucleic acid analogues not present in nature that can be used for the storage of genetic information. In vivo XNA applications could be developed into novel biocontainment strategies, but are currently limited by the challenge of developing XNA processing enzymes such as polymerases, ligases and nucleases. Here, we present a structure-guided modelling-based strategy for the rational design of those enzymes essential for the development of XNA molecular biology. Docking of protein domains to unbound double-stranded nucleic acids is used to generate a first approximation of the extensive interaction of nucleic acid processing enzymes with their substrate. Molecular dynamics is used to optimise that prediction allowing, for the first time, the accurate prediction of how proteins that form toroidal complexes with nucleic acids interact with their substrate. Using the Chlorella virus DNA ligase as a proof of principle, we recapitulate the ligase’s substrate specificity and successfully predict how to convert it into an XNA-templated XNA ligase.
| Type: | Article |
|---|---|
| Title: | Rational design of an XNA ligase through docking of unbound nucleic acids to toroidal proteins |
| Location: | England |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1093/nar/gkz551 |
| Publisher version: | https://doi.org/10.1093/nar/gkz551 |
| Language: | English |
| Additional information: | This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Structural and Molecular Biology |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10079006 |
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