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

Ivana Drienovská, Lur Alonso-Cotchico, Pietro Vidossich, Agustí Lledós, Jean Didier Maréchal, Gerard Roelfes

Research output: Contribution to journalArticleResearchpeer-review

45 Citations (Scopus)

Abstract

© 2017 The Royal Society of Chemistry. 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.
Original languageEnglish
Pages (from-to)7228-7235
JournalChemical Science
Volume8
Issue number10
DOIs
Publication statusPublished - 1 Jan 2017

Fingerprint

Dive into the research topics of 'Design of an enantioselective artificial metallo-hydratase enzyme containing an unnatural metal-binding amino acid'. Together they form a unique fingerprint.

Cite this