Structures of DPAGT1 explain glycosylation disease mechanisms and advance TB antibiotic design

Structures of DPAGT1 explain glycosylation disease mechanisms and advance TB antibiotic design

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 glyco...

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Bibliographic Details
Main Authors: Dong, YY, Wang, H, Pike, ACW, Cochrane, SA, Hamedzadeh, S, Wyszyński, FJ, Bushell, SR, Royer, SF, Widdick, DA, Sajid, A, Boshoff, HI, Park, Y, Lucas, R, Liu, W-M, Lee, SS, Machida, T, Minall, L, Mehmood, S, Belaya, K, Liu, W-W, Chu, A, Shrestha, L, Mukhopadhyay, SMM, Strain-Damerell, C, Chalk, R, Burgess-Brown, NA, Bibb, MJ, Barry, CE, Robinson, CV, Beeson, D, Davis, BG, Carpenter, EP
Format: Journal article
Language:English
Published: Elsevier 2018
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Summary: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.

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