Exotoxin A-eEF2 complex structure indicates ADP ribosylation by ribosome mimicry
Exotoxin A-eEF2 complex structure indicates ADP ribosylation by ribosome mimicry
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DOI：
10.1038/nature03871
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发表时间：
2005-08-18
期刊：
影响因子：
64.8
通讯作者：
Andersen, GR
中科院分区：
文献类型：
--
作者：
Jorgensen, R;Merrill, AR;Andersen, GR
引起白喉、百日咳、霍乱和其他疾病的细菌分泌单ADP核糖基化毒素，修饰细胞内蛋白质。在这里，我们描述了四种结构的催化活性复合物之间的片段的铜绿假单胞菌外毒素A（ETA）和它的蛋白质底物，翻译延伸因子2（eEF 2）。eEF 2中的目标残基，双苯二甲酰胺（一种修饰的组氨酸），跨越一个裂缝，面对两个磷酸盐和一个核糖的不可水解的NAD（+）类似物，β-内酰胺。这表明，在亲核取代反应期间，二苯二甲酰胺参与触发NAD（+）裂解并与所提出的氧杂卡宾中间体相互作用，从而解释了ADP核糖基化需要二苯二甲酰胺。白喉毒素可以以类似于ETA的方式识别eEF 2。值得注意的是，毒素结合的β EF 2磷酸模拟18 S rRNA构象转换中两个核苷酸的磷酸骨架，从而实现ETA对eEF 2的普遍识别。
The bacteria causing diphtheria, whooping cough, cholera and other diseases secrete mono-ADP-ribosylating toxins that modify intracellular proteins. Here, we describe four structures of a catalytically active complex between a fragment of Pseudomonas aeruginosa exotoxin A (ETA) and its protein substrate, translation elongation factor 2 (eEF2). The target residue in eEF2, diphthamide (a modified histidine), spans across a cleft and faces the two phosphates and a ribose of the non-hydrolysable NAD(+) analogue, beta TAD. This suggests that the diphthamide is involved in triggering NAD(+) cleavage and interacting with the proposed oxacarbenium intermediate during the nucleophilic substitution reaction, explaining the requirement of diphthamide for ADP ribosylation. Diphtheria toxin may recognize eEF2 in a manner similar to ETA. Notably, the toxin-bound beta TAD phosphates mimic the phosphate backbone of two nucleotides in a conformational switch of 18S rRNA, thereby achieving universal recognition of eEF2 by ETA.