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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DOI：
10.1016/j.cell.2018.10.037
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发表时间：
2018-11-01
期刊：
影响因子：
64.5
通讯作者：
Carpenter EP
中科院分区：
文献类型：
--
作者：
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 WM;Lee SS;Machida T;Minall L;Mehmood S;Belaya K;Liu WW;Chu A;Shrestha L;Mukhopadhyay SMM;Strain-Damerell C;Chalk R;Burgess-Brown NA;Bibb MJ;Barry Iii CE;Robinson CV;Beeson D;Davis BG;Carpenter EP
蛋白质n -糖基化是一种广泛的翻译后修饰。该过程的第一步是由多酰磷酸n -乙酰氨基葡萄糖-磷酸转移酶DPAGT1 （GPT/E.C.）催化2.7.8.15)。错义DPAGT1变异引起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tunicamycin，由于DPAGT1抑制，对真核生物有毒性，阻碍了它们的临床应用。我们的DPAGT1与底物UDP-GlcNAc和tunicamycin的结构揭示了底物结合模式，提示了催化机制，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”的tunicamycin。这些类似物针对几种细菌靶点的结构调整活性允许设计有效的结核分枝杆菌抗生素，使体外、细胞内和体内治疗成为可能，提供了一种有前途的新型抗菌药物。DPAGT1与UDP-GlcNAc和tunicamycin的结构揭示糖基化障碍患者DPAGT1突变的催化机制调节DPAGT1活性结构、动力学和生物合成揭示脂质在tunicamycin脂质改变中的作用从结构上了解tunicamycin与人类n-链糖基化途径的毒性相互作用，可以鉴定出对小鼠结核病有效的无毒抗生素
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. Structures of DPAGT1 with UDP-GlcNAc and tunicamycin reveal mechanisms of catalysis DPAGT1 mutations in patients with glycosylation disorders modulate DPAGT1 activity Structures, kinetics and biosynthesis reveal role of lipid in tunicamycin Lipid-altered, tunicamycin analogues give non-toxic antibiotics against TB Structural insights into tunicamycin’s toxic interactions with the human N-linked glycosylation pathway allows the identification of non-toxic antibiotics effective against tuberculosis in mice
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DOI：
10.1107/s0907444905036693
发表时间：
2006-01-01
影响因子：
2.2
作者：
Evans, P
通讯作者：
Evans, P
DOI：
10.1126/science.1236501
发表时间：
2013-08-30
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Chung BC;Zhao J;Gillespie RA;Kwon DY;Guan Z;Hong J;Zhou P;Lee SY
通讯作者：
Lee SY
影响因子：
14.8
作者：
Kelley LA;Mezulis S;Yates CM;Wass MN;Sternberg MJ
通讯作者：
Sternberg MJ
影响因子：
2
作者：
Arroyo Carrera, Ignacio;Matthijs, Gert;Perez Cerda, Celia
通讯作者：
Perez Cerda, Celia
DOI：
10.1073/pnas.1404099111
发表时间：
2014-08-26
影响因子：
11.1
作者：
Maria, John P. Santa, Jr.;Sadaka, Ama;Walker, Suzanne
通讯作者：
Walker, Suzanne