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Rational design of an XNA ligase through docking of unbound nucleic acids to toroidal proteins.
Vanmeert, Michiel; Razzokov, Jamoliddin; Mirza, Muhammad Usman; Weeks, Stephen D; Schepers, Guy; Bogaerts, Annemie; Rozenski, Jef; Froeyen, Mathy; Herdewijn, Piet; Pinheiro, Vitor B; Lescrinier, Eveline.
Afiliación
  • Vanmeert M; Medicinal Chemistry, Rega Institute for Medical Research, KU Leuven, Herestraat 49, box 1041, 3000 Leuven, Belgium.
  • Razzokov J; Research group PLASMANT, Department of Chemistry, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium.
  • Mirza MU; Medicinal Chemistry, Rega Institute for Medical Research, KU Leuven, Herestraat 49, box 1041, 3000 Leuven, Belgium.
  • Weeks SD; Centre for Research in Molecular Medicine (CRiMM), University of Lahore, Pakistan.
  • Schepers G; Biocrystallography, KU Leuven, Herestraat 49, box 822, 3000 Leuven, Belgium.
  • Bogaerts A; Medicinal Chemistry, Rega Institute for Medical Research, KU Leuven, Herestraat 49, box 1041, 3000 Leuven, Belgium.
  • Rozenski J; Research group PLASMANT, Department of Chemistry, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium.
  • Froeyen M; Medicinal Chemistry, Rega Institute for Medical Research, KU Leuven, Herestraat 49, box 1041, 3000 Leuven, Belgium.
  • Herdewijn P; Medicinal Chemistry, Rega Institute for Medical Research, KU Leuven, Herestraat 49, box 1041, 3000 Leuven, Belgium.
  • Pinheiro VB; Medicinal Chemistry, Rega Institute for Medical Research, KU Leuven, Herestraat 49, box 1041, 3000 Leuven, Belgium.
  • Lescrinier E; Medicinal Chemistry, Rega Institute for Medical Research, KU Leuven, Herestraat 49, box 1041, 3000 Leuven, Belgium.
Nucleic Acids Res ; 47(13): 7130-7142, 2019 07 26.
Article en En | MEDLINE | ID: mdl-31334814
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: ADN Ligasas / Proteínas Virales Tipo de estudio: Prognostic_studies Idioma: En Revista: Nucleic Acids Res Año: 2019 Tipo del documento: Article País de afiliación: Bélgica Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: ADN Ligasas / Proteínas Virales Tipo de estudio: Prognostic_studies Idioma: En Revista: Nucleic Acids Res Año: 2019 Tipo del documento: Article País de afiliación: Bélgica Pais de publicación: Reino Unido