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首页> 外文期刊>Biochemistry >Biologically important conformations of aminoglycoside antibiotics bound to an aminoglycoside 3'-phosphotransferase as determined by transferred nuclear Overhauser effect spectroscopy.
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Biologically important conformations of aminoglycoside antibiotics bound to an aminoglycoside 3'-phosphotransferase as determined by transferred nuclear Overhauser effect spectroscopy.

机译：通过转移核富豪效应光谱法测定的氨基糖苷抗生素与氨基糖苷脂3'-磷酸转移酶结合的生物学上重要的构象。

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摘要

NMR spectroscopy has been used to study the interaction of aminoglycoside antibiotics with an aminoglycoside antibiotic 3'-phosphotransferase [APH(3')-IIIa]. APH(3')-IIIa is an enterococcal enzyme that is responsible for the ATP-dependent O-phosphorylation of a broad range of aminoglycoside antibiotics. The NMR method of transferred nuclear Overhauser effect spectroscopy (TRNOESY) was used to detect intra- and inter-ring NOEs for butirosin A and amikacin in their respective ternary complexes with APH(3')-IIIa and ATP. NOE-derived distance constraints were used in energy minimization and dynamics routines to yield enzyme-bound structures for butirosin A. These structures suggest that the 2,6-diamino-2,6-dideoxy-D-glucose and D-xylose rings have restricted motions and are in a stacking arrangement. The TRNOE spectra for amikacin suggest that the 6-amino-6-deoxy-D-glucose ring is flexible when the antibiotic is bound to APH(3')-IIIa. The 15N resonances of butirosin A were assigned and the pKa values of the amino groups of butirosin A and amikacin were determined by 15N NMR spectroscopy. The N3 amino groups of butirosin A and amikacin have lowered pKa values, which is attributed to the (S)-4-amino-2-hydroxybutyryl (AHB) group of the antibiotics. This work provides an insight into the geometrical and electrostatic nature of aminoglycoside antibiotics bound to a modifying enzyme and will provide a basis for the design of inhibitors of APH(3')-IIIa.
机译：已经使用NMR光谱研究氨基糖苷类抗生素与氨基糖苷类抗生素3'-磷酸转移酶的相互作用[APH（3'） - IIIa]。 APH（3'） - IIIa是一种肠球菌酶，其负责ATP依赖性O-磷酸化的广泛的氨基糖苷类抗生素。转移核掺杂效应光谱（TRNOOSY）的NMR方法用于用APH（3'） - IIIA和ATP在其各自的三元复合物中检测丁蛋白A和Amikacin的内圈和间隙。 NOE衍生的距离约束用于能量最小化和动力学常规，以产生丁素A的酶结合结构。这些结构表明，2,6-二氨基-2,6-双氧化-D-葡萄糖和D-木糖环限制了动作，并处于堆叠安排。 Amikacin的Trnoe光谱表明，当抗生素与APH（3'） - IIIa结合时，6-氨基-6-脱氧-D-葡萄糖环是柔韧的。分配了丁蛋白A的15N共振，并通过15N NMR光谱法测定丁素A和Amikacin的氨基的PKA值。丁素A和Amikacin的N3氨基具有降低的PKA值，其归因于抗生素的（S）-4-氨基-2-羟基丁基（AHB）基团。这项工作介绍了氨基糖苷类抗生素的几何和静电性质，其结合到改性酶，并将为APH（3'） - IIIa的抑制剂的设计提供依据。

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