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De novo active sites for resurrected Precambrian enzymes
Univ Granada, Fac Ciencias, Dept Quim Fis, E-18071 Granada, Spain..
Univ Granada, Fac Ciencias, Dept Quim Fis, E-18071 Granada, Spain..
Univ Granada, Fac Ciencias, Dept Quim Fis, E-18071 Granada, Spain..
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Structure and Molecular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
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2017 (English)In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 8, article id 16113Article in journal (Refereed) Published
Abstract [en]

Protein engineering studies often suggest the emergence of completely new enzyme functionalities to be highly improbable. However, enzymes likely catalysed many different reactions already in the last universal common ancestor. Mechanisms for the emergence of completely new active sites must therefore either plausibly exist or at least have existed at the primordial protein stage. Here, we use resurrected Precambrian proteins as scaffolds for protein engineering and demonstrate that a new active site can be generated through a single hydrophobic-to-ionizable amino acid replacement that generates a partially buried group with perturbed physico-chemical properties. We provide experimental and computational evidence that conformational flexibility can assist the emergence and subsequent evolution of new active sites by improving substrate and transition-state binding, through the sampling of many potentially productive conformations. Our results suggest a mechanism for the emergence of primordial enzymes and highlight the potential of ancestral reconstruction as a tool for protein engineering.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP , 2017. Vol. 8, article id 16113
National Category
Biological Sciences
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URN: urn:nbn:se:uu:diva-331231DOI: 10.1038/ncomms16113ISI: 000405728000001PubMedID: 28719578OAI: oai:DiVA.org:uu-331231DiVA, id: diva2:1149491
Funder
EU, FP7, Seventh Framework Programme, 306474
Available from: 2017-10-16 Created: 2017-10-16 Last updated: 2017-11-29Bibliographically approved

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Krüger, Dennis M.Kamerlin, Shina C. Lynn
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