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Issue 10, 2017
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Design of an enantioselective artificial metallo-hydratase enzyme containing an unnatural metal-binding amino acid

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Abstract

The design of artificial metalloenzymes is a challenging, yet ultimately highly rewarding objective because of the potential for accessing new-to-nature reactions. One of the main challenges is identifying catalytically active substrate–metal cofactor–host geometries. The advent of expanded genetic code methods for the in vivo incorporation of non-canonical metal-binding amino acids into proteins allow to address an important aspect of this challenge: the creation of a stable, well-defined metal-binding site. Here, we report a designed artificial metallohydratase, based on the transcriptional repressor lactococcal multidrug resistance regulator (LmrR), in which the non-canonical amino acid (2,2′-bipyridin-5yl)alanine is used to bind the catalytic Cu(II) ion. Starting from a set of empirical pre-conditions, a combination of cluster model calculations (QM), protein–ligand docking and molecular dynamics simulations was used to propose metallohydratase variants, that were experimentally verified. The agreement observed between the computationally predicted and experimentally observed catalysis results demonstrates the power of the artificial metalloenzyme design approach presented here.

Graphical abstract: Design of an enantioselective artificial metallo-hydratase enzyme containing an unnatural metal-binding amino acid

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Publication details

The article was received on 09 Aug 2017, accepted on 01 Sep 2017 and first published on 04 Sep 2017


Article type: Edge Article
DOI: 10.1039/C7SC03477F
Citation: Chem. Sci., 2017,8, 7228-7235
  • Open access: Creative Commons BY-NC license
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    Design of an enantioselective artificial metallo-hydratase enzyme containing an unnatural metal-binding amino acid

    I. Drienovská, L. Alonso-Cotchico, P. Vidossich, A. Lledós, J. Maréchal and G. Roelfes, Chem. Sci., 2017, 8, 7228
    DOI: 10.1039/C7SC03477F

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