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Protein N-glycosylation is a widespread post-translational modification. The first committed step in this process is catalysed by dolichyl-phosphate N-acetylglucosamine-phosphotransferase DPAGT1 (GPT/E.C. 2.7.8.15). Missense DPAGT1 variants cause congenital myasthenic syndrome and disorders of glycosylation. In addition, naturally-occurring bactericidal nucleoside analogues such as tunicamycin are toxic to eukaryotes due to DPAGT1 inhibition, preventing their clinical use. Our structures of DPAGT1 with the substrate UDP-GlcNAc and tunicamycin reveal substrate binding modes, suggest a mechanism of catalysis, provide an understanding of how mutations modulate activity (thus causing disease) and allow design of non-toxic "lipid-altered" tunicamycins. The structure-tuned activity of these analogues against several bacterial targets allowed the design of potent antibiotics for Mycobacterium tuberculosis, enabling treatment in vitro, in cellulo and in vivo, providing a promising new class of antimicrobial drug.

Original publication

DOI

10.1016/j.cell.2018.10.037

Type

Journal article

Journal

Cell

Publication Date

01/11/2018

Volume

175

Pages

1045 - 1058.e16

Keywords

DPAGT1, GPT, Protein N-glycosylation, congenital disorders of glycosylation, congenital myasthenic syndrome, tunicamycin, Animals, Antibiotics, Antitubercular, Binding Sites, Congenital Disorders of Glycosylation, Enzyme Inhibitors, Female, HEK293 Cells, Hep G2 Cells, Humans, Lipid Metabolism, Mice, Molecular Docking Simulation, Mutation, N-Acetylglucosaminyltransferases, Protein Binding, Sf9 Cells, Spodoptera, Tunicamycin, Uridine Diphosphate Glucuronic Acid