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Structural basis for the diversity of the mechanism of nucleotide hydrolysis by the aminoglycoside-2''-phosphotransferases.
Acta Crystallographica Section D ( IF 2.6 ) Pub Date : 2019-12-03 , DOI: 10.1107/s2059798319015079
Clyde A Smith 1 , Marta Toth 2 , Nichole K Stewart 2 , Lauren Maltz 1 , Sergei B Vakulenko 2
Affiliation  

Aminoglycoside phosphotransferases (APHs) are one of three families of aminoglycoside‐modifying enzymes that confer high‐level resistance to the aminoglycoside antibiotics via enzymatic modification. This has now rendered many clinically important drugs almost obsolete. The APHs specifically phosphorylate hydroxyl groups on the aminoglycosides using a nucleotide triphosphate as the phosphate donor. The APH(2′′) family comprises four distinct members, isolated primarily from Enterococcus sp., which vary in their substrate specificities and also in their preference for the phosphate donor (ATP or GTP). The structure of the ternary complex of APH(2′′)‐IIIa with GDP and kanamycin was solved at 1.34 Å resolution and was compared with substrate‐bound structures of APH(2′′)‐Ia, APH(2′′)‐IIa and APH(2′′)‐IVa. In contrast to the case for APH(2′′)‐Ia, where it was proposed that the enzyme‐mediated hydrolysis of GTP is regulated by conformational changes in its N‐terminal domain upon GTP binding, APH(2′′)‐IIa, APH(2′′)‐IIIa and APH(2′′)‐IVa show no such regulatory mechanism, primarily owing to structural differences in the N‐terminal domains of these enzymes.

中文翻译:


氨基糖苷-2''-磷酸转移酶水解核苷酸机制多样性的结构基础。



氨基糖苷类磷酸转移酶 (APH) 是氨基糖苷类修饰酶的三个家族之一,可通过酶修饰赋予对氨基糖苷类抗生素的高水平耐药性。这使得许多临床上重要的药物几乎过时。 APH 使用三磷酸核苷酸作为磷酸盐供体,特异性磷酸化氨基糖苷上的羟基。 APH(2'') 家族包括四个不同的成员,主要从肠球菌属中分离出来,它们的底物特异性以及对磷酸盐供体(ATP 或 GTP)的偏好各不相同。以 1.34 Å 分辨率解析了 APH(2′′)-IIIa 与 GDP 和卡那霉素的三元复合物的结构,并与 APH(2′′)-Ia、APH(2′′)- 的底物结合结构进行了比较IIa 和 APH(2′′)-IVa。与 APH(2'')-Ia 的情况相反,其中提出酶介导的 GTP 水解是通过 GTP 结合时其 N 末端结构域的构象变化来调节的,APH(2'')-IIa 、APH(2'')-IIIa 和 APH(2'')-IVa 没有表现出这样的调节机制,主要是由于这些酶的 N 末端结构域的结构差异。
更新日期:2019-12-03
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