Analysis of the π-π stacking interactions between the aminoglycoside antibiotic kinase APH(3′)-IIIa and its nucleotide ligands
Analysis of the π-π stacking interactions between the aminoglycoside antibiotic kinase APH(3′)-IIIa and its nucleotide ligands
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DOI：
10.1016/s1074-5521(02)00245-4
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发表时间：
2002-11-01
影响因子：
--
通讯作者：
Cox, JR
中科院分区：
文献类型：
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作者：
Boehr, DD;Farley, AR;Cox, JR
氨基糖苷磷酸转移酶（APH（3 '）-IIIa）活性位点中的关键接触是Tyr 42与结合核苷酸的腺嘌呤环之间的pi-pi堆积相互作用。我们调查了相似的Tyr-腺嘌呤接触的普遍性，发现许多不同的蛋白质系统在腺嘌呤环的识别中使用Tyr残基。这些堆积相互作用的几何形状表明，静电在这些芳香族系统之间的吸引力中发挥作用。对野生型和突变型APH（3 '）-IIIa的动力学和量热实验进一步证明了静电在腺嘌呤结合区的重要性，并表明堆积相互作用贡献了约2 kcal/mol的结合能。关于APH（3 '）-IIIa中控制核苷酸结合的力的这种类型的信息将促进靶向APH型酶的核苷酸结合位点的抑制剂设计策略。
A key contact in the active site of an aminoglycoside phosphotransferase enzyme (APH(3')-IIIa) is a pi-pi stacking interaction between Tyr42 and the adenine ring of bound nucleotides. We investigated the prevalence of similar Tyr-adenine contacts and found that many different protein systems employ Tyr residues in the recognition of the adenine ring. The geometry of these stacking interactions suggests that electrostatics play a role in the attraction between these aromatic systems. Kinetic and calorimetric experiments on wild-type and mutant forms of APH(3')-IIIa yielded further experimental evidence of the importance of electrostatics in the adenine binding region and suggested that the stacking interaction contributes similar to2 kcal/mol of binding energy. This type of information concerning the forces that govern nucleotide binding in APH(3')-IIIa will facilitate inhibitor design strategies that target the nucleotide binding site of APH-type enzymes.