Structures of DPAGT1 explain glycosylation disease mechanisms and advance TB antibiotic design
Structures of DPAGT1 explain glycosylation disease mechanisms and advance TB antibiotic design
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DPAGT1 的结构解释了糖基化疾病机制并推进结核病抗生素设计
DOI：
10.1101/291278
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发表时间：
2018
期刊：
影响因子：
--
通讯作者：
Dong Y
中科院分区：
文献类型：
--
作者：
Dong Y
蛋白质N-糖基化是一种广泛的翻译后修饰。该过程中的第一个关键步骤是由多羟磷酸N-乙酰葡萄糖胺磷酸转移酶DPAGT 1（GPT/EC）催化的2.7.8.15）。错义DPAGT 1变体导致先天性肌无力综合征和糖基化障碍。此外，天然存在的杀菌核苷类似物如衣霉素由于DPAGT 1抑制而对真核生物有毒，从而阻止了它们的临床应用。我们的DPAGT 1与底物UDP-GlcNAc和衣霉素的结构揭示了底物结合模式，提出了催化机制，提供了突变如何调节活性（从而引起疾病）的理解，并允许设计无毒的“脂质改变”衣霉素。这些类似物对几种细菌靶点的结构调节活性允许设计针对结核分枝杆菌的有效抗生素，使体外，纤维素和体内治疗成为可能，提供了一类有前途的新型抗菌药物。
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 forMycobacterium tuberculosis, enabling treatmentin vitro,in celluloandin vivo,providing a promising new class of antimicrobial drug.