Web of Science: 26 cites, Scopus: 27 cites, Google Scholar: cites
Design of an enantioselective artificial metallo-hydratase enzyme containing an unnatural metal-binding amino acid
Drienovská, Ivana (Stratingh Institute for Chemistry)
Alonso-Cotchico, Lur (Universitat Autònoma de Barcelona. Departament de Química)
Vidossich, Pietro (Universitat Autònoma de Barcelona. Departament de Química)
Lledós, Agustí (Lledós i Falcó) (Universitat Autònoma de Barcelona. Departament de Química)
Maréchal, Jean-Didier (Universitat Autònoma de Barcelona. Departament de Química)
Roelfes, Gerard (Stratingh Institute for Chemistry)

Data: 2017
Resum: Starting from biochemical knowledge followed by computational design, an artificial metallo-hydratase comprising an unnatural metal binding amino acid was created. 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() 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.
Nota: Número d'acord de subvenció EC/FP7/280010
Nota: Número d'acord de subvenció MINECO/CTQ2014-54071-P
Nota: Número d'acord de subvenció AGAUR/2014/SGR-989
Drets: Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original. Creative Commons
Llengua: Anglès.
Document: article ; recerca ; publishedVersion
Publicat a: Chemical science, Vol. 8 (Oct. 2017) , p. 7228-7235, ISSN 2041-6539

PMID: 29081955
DOI: 10.1039/c7sc03477f

8 p, 830.0 KB

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