Structural Insights into Pseudomonas aeruginosa Exotoxin A-Elongation Factor 2 Interactions: A Molecular Dynamics Study.
Structural Insights into Pseudomonas aeruginosa Exotoxin A-Elongation Factor 2 Interactions: A Molecular Dynamics Study.
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DOI：
10.1021/acs.jcim.3c00064
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发表时间：
2023-03-13
影响因子：
5.6
通讯作者：
Eriksson LA
中科院分区：
文献类型：
--
作者：
Gholami A;Minai-Tehrani D;Mahdizadeh SJ;Saenz-Mendez P;Eriksson LA
外毒素A(ExooxinA，ETA)是由铜绿假单胞菌产生的一种胞外分泌性毒素，是一种含有A、B片段的单链多肽。它催化翻译后修饰的组氨酸(敌草胺)与真核生物延长因子2(EEF2)的ADP核糖基化，导致eEF2失活，抑制蛋白质的生物合成。研究表明，二苯胺咪唑环在毒素催化的ADP-核糖化反应中起着重要作用。在这项工作中，我们使用不同的分子动力学(MD)模拟方法来了解eEF2中双苯二甲胺和未经修饰的组氨酸在与ETA相互作用中的作用。在联苯二甲胺和组氨酸体系中，选择并比较了三种不同配体NAD+、腺苷二磷酸核糖和βTAD的eEF2-eta配合物的晶体结构。研究表明，与其他配体相比，与ETA结合的NAD+非常稳定，在核糖化过程中，ADP-核糖能够转移到eEF2中二苯胺咪唑环的N3原子上。我们还表明，eEF2中未修饰的组氨酸对ETA结合有负面影响，不适合ADP-核糖的结合。对NAD+、β-TAD和ADP-核糖配合物的回转半径和COM距离的分析表明，在整个MD模拟过程中，未修饰的His影响了结构并破坏了所有不同配体的配合物的稳定性。
Exotoxin A (ETA) is an extracellular secreted toxin and a single-chain polypeptide with A and B fragments that is produced by Pseudomonas aeruginosa. It catalyzes the ADP-ribosylation of a post-translationally modified histidine (diphthamide) on eukaryotic elongation factor 2 (eEF2), which results in the inactivation of the latter and the inhibition of protein biosynthesis. Studies show that the imidazole ring of diphthamide plays an important role in the ADP-ribosylation catalyzed by the toxin. In this work, we employ different in silico molecular dynamics (MD) simulation approaches to understand the role of diphthamide versus unmodified histidine in eEF2 on the interaction with ETA. Crystal structures of the eEF2–ETA complexes with three different ligands NAD+, ADP-ribose, and βTAD were selected and compared in the diphthamide and histidine containing systems. The study shows that NAD+ bound to ETA remains very stable in comparison with other ligands, enabling the transfer of ADP-ribose to the N3 atom of the diphthamide imidazole ring in eEF2 during ribosylation. We also show that unmodified histidine in eEF2 has a negative impact on ETA binding and is not a suitable target for the attachment of ADP-ribose. Analyzing of radius of gyration and COM distances for NAD+, βTAD, and ADP-ribose complexes revealed that unmodified His affects the structure and destabilizes the complex with all different ligands throughout the MD simulations.
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影响因子：
6.4
作者：
LIU, PV
通讯作者：
LIU, PV
影响因子：
64.8
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Jorgensen, R;Merrill, AR;Andersen, GR
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JORGENSEN, WL;CHANDRASEKHAR, J;KLEIN, ML
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