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首页> 外文期刊>Acta crystallographica, Section D. Biological crystallography >The structure of apo ArnA features an unexpected central binding pocket and provides an explanation for enzymatic cooperativity
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The structure of apo ArnA features an unexpected central binding pocket and provides an explanation for enzymatic cooperativity

机译：载脂蛋白ArnA的结构具有意外的中央结合袋，并为酶促协同作用提供了解释

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摘要

The bacterial protein ArnA is an essential enzyme in the pathway leading to the modification of lipid A with the pentose sugar 4-amino-4-deoxy-l-arabinose. This modification confers resistance to polymyxins, which are antibiotics that are used as a last resort to treat infections with multiple drug-resistant Gram-negative bacteria. ArnA contains two domains with distinct catalytic functions: a dehydrogenase domain and a transformylase domain. The protein forms homohexamers organized as a dimer of trimers. Here, the crystal structure of apo ArnA is presented and compared with its ATP- and UDP-glucuronic acid-bound counterparts. The comparison reveals major structural rearrangements in the dehydrogenase domain that lead to the formation of a previously unobserved binding pocket at the centre of each ArnA trimer in its apo state. In the crystal structure, this pocket is occupied by a DTT molecule. It is shown that formation of the pocket is linked to a cascade of structural rearrangements that emerge from the NAD(+)-binding site. Based on these findings, a small effector molecule is postulated that binds to the central pocket and modulates the catalytic properties of ArnA. Furthermore, the discovered conformational changes provide a mechanistic explanation for the strong cooperative effect recently reported for the ArnA dehydrogenase function.
机译：细菌蛋白ArnA是导致戊糖4-氨基-4-脱氧-1-阿拉伯糖修饰脂质A的途径中的必需酶。这种修饰赋予了对多粘菌素的抗性，多粘菌素是抗生素，可用于治疗多种耐药革兰氏阴性细菌的感染。 ArnA包含两个具有不同催化功能的结构域：脱氢酶结构域和转化酶结构域。蛋白质形成组织为三聚体二聚体的同型六聚体。在这里，介绍了载脂蛋白ArnA的晶体结构，并将其与ATP和UDP-葡萄糖醛酸结合的对应物进行比较。该比较揭示了脱氢酶结构域中的主要结构重排，其导致在其载脂蛋白状态的每个ArnA三聚体的中心形成先前未被观察到的结合口袋。在晶体结构中，该口袋被DTT分子占据。结果表明，口袋的形成与从NAD（+）结合位点出现的结构重排的级联有关。基于这些发现，推测有一个小的效应分子与中央口袋结合并调节ArnA的催化性能。此外，发现的构象变化为最近报道的ArnA脱氢酶功能的强协同作用提供了机理解释。

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