期刊
CELL
卷 175, 期 4, 页码 1045-+出版社
CELL PRESS
DOI: 10.1016/j.cell.2018.10.037
关键词
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资金
- AbbVie (United States) [1097737]
- Bayer Pharma AG (Germany)
- Canada Foundation for Innovation (Canada)
- Eshelman Institute for Innovation (Canada)
- Innovative Medicines Initiative (EU/EFPIA) (United States) [115766]
- Janssen (United States)
- Merck KGaA Darmstadt Germany
- Novartis Pharma AG (Switzerland)
- Ontario Ministry of Economic Development and Innovation (Canada)
- Pfizer (United States)
- Wellcome (United Kingdom) [106169/Z/14/Z]
- Gates Foundation (United Kingdom)
- BBSRC (United Kingdom)
- EPSRC (United Kingdom)
- Wellcome [110270/A/15/Z]
- MRC (United Kingdom) programme [MR/N020413/1]
- MRC [MR/M006824]
- Wellcome Strategic Award [WT084655MA]
- BBSRC [BB/J006637/1, BB/J009725/1, BB/J004561/1]
- Intramural Research Program of NIAID
- Boehringer Ingelheim (Germany)
- Genome Canada (Canada)
- MSD (USA)
- Sao Paulo Research Foundation-FAPESP (Brazil)
- Takeda (Japan)
- Evotec Ltd
- Wellcome Trust [106169/Z/14/Z] Funding Source: Wellcome Trust
- BBSRC [BB/J009725/1, BB/J006637/1] Funding Source: UKRI
- MRC [MR/M006824/1, MR/N020413/1] Funding Source: UKRI
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 eu-karyotes 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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