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Structure-based recombination of drug resistance enzymes: structural and functional tolerance to new dynamics in artificially-evolved enzymes

Gobeil, Sophie; Park, Jaeok; Ebert, Maximilian; Gagné, Donald; Clouthier, Christopher M.; Pleiss, Jürgen; Doucet, Nicolas; Berghuis, Albert M. et Pelletier, Joelle N. . Structure-based recombination of drug resistance enzymes: structural and functional tolerance to new dynamics in artificially-evolved enzymes In: 2nd Protein Engineering Canada Conference (PEC), 17-19 Juin 2016, Ottawa, Canada.

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Résumé

Our understanding of the contribution of protein dynamics to fu nction is still emergent. In a protein engineering context, do we need to take into account the dynami cs in order to maximize the fitness and function of the resulting proteins? Using high resolution c rystal structures, NMR relaxation dispersion and μs molecular dynamics simulations, we compare tw o naturally evolved homologous class A β-lactamases, TEM-1 and PSE-4 which share a high degree of structural and functional conservation. We observed a conservation of restrict ed dynamics on a catalytically relevant timescale. This is consistent with dynamics being an e volutionarily conserved feature. However, laboratory-engineered chimeric enzymes obtained by rec ombination of the two homologs exhibit striking dynamic differences, despite the func tion and structure being conserved. The laboratory-engineered chimeras are thus functionally and st ructurally tolerant to modified dynamics on the timescale of the catalytic turnover. This toler ance of β-lactamases to dynamic changes could be linked to the high fitness of the naturally ev olved proteins and implies that maintenance of native-like protein dynamics may not be essentia l when engineering functional proteins.

Type de document: Document issu d'une conférence ou d'un atelier
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Centre: Centre INRS-Institut Armand Frappier
Date de dépôt: 16 août 2018 02:36
Dernière modification: 16 août 2018 02:36
URI: https://espace.inrs.ca/id/eprint/5795

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