Structural characterization and computer-aided redesign of the substrate binding pockets of the selection domains from mega-enzymes involved in glycopeptide antibiotic biosynthesis

Teicoplanin is a glycopeptide antibiotic (GPAs)used to treat infections by Gram-positive bacterial pathogens. GPAs are natural products and due to their complex structure we rely on bacterial fermentation for their production. Consequently, we need to understand GPA biosynthesis to develop new compounds for clinical use. Herein, we structurally characterise an amino acid selection domain integral to the synthesis of the GPA, explore the evolution of these domains to reveal how ancestral forms of these proteins evolved to accept new amino acid building blocks, and learn how to modify these domains by understanding natural evolution in biosynthesis.