Crystal structures of two aminoglycoside kinases bound with a eukaryotic protein kinase inhibitor.
Crystal structures of two aminoglycoside kinases bound with a eukaryotic protein kinase inhibitor.
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DOI：
10.1371/journal.pone.0019589
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发表时间：
2011-05-09
期刊：
影响因子：
3.7
通讯作者：
Berghuis AM
中科院分区：
文献类型：
--
作者：
Fong DH;Xiong B;Hwang J;Berghuis AM
抗生素耐药性被认为是一个日益严重的医疗保健问题。为了解决这个问题，一种策略是使用佐剂与抗生素一起阻止因果机制。氨基糖苷类抗生素是一类临床上重要的抗生素，用于治疗严重感染。它们的有用性已受到损害，主要是由于药物失活的氨基糖苷类修饰酶，如氨基糖苷磷酸转移酶或激酶。这些激酶在结构上与真核生物的Ser/Thr和Tyr蛋白激酶同源，并且已经显示一些激酶可以被选择的蛋白激酶抑制剂抑制。氨基糖苷激酶APH（3′）-IIIa可被CKI-7抑制，CKI-7是酪蛋白激酶1的ATP竞争性抑制剂。我们已经确定CKI-7也是非典型APH（9）-Ia的中度抑制剂。在这里，我们展示了CKI-7结合的APH（3′）-IIIa和APH（9）-Ia的晶体结构，这是与细菌激酶复合的真核蛋白激酶抑制剂的第一种结构。CKI-7与酶的核苷酸结合口袋结合，其结合改变了核苷酸结合环的构象，该片段与神经元蛋白激酶中富含甘氨酸的环同源。这些结构与CKI-7结合的酪蛋白激酶1的比较揭示了在细菌激酶中不同的结合口袋中的特征，并且可以用于设计细菌激酶特异性抑制剂。我们的研究结果提供的证据表明，一个子集的APHs的抑制剂可以开发，以减少耐药性的氨基糖苷类。
Antibiotic resistance is recognized as a growing healthcare problem. To address this issue, one strategy is to thwart the causal mechanism using an adjuvant in partner with the antibiotic. Aminoglycosides are a class of clinically important antibiotics used for the treatment of serious infections. Their usefulness has been compromised predominantly due to drug inactivation by aminoglycoside-modifying enzymes, such as aminoglycoside phosphotransferases or kinases. These kinases are structurally homologous to eukaryotic Ser/Thr and Tyr protein kinases and it has been shown that some can be inhibited by select protein kinase inhibitors. The aminoglycoside kinase, APH(3′)-IIIa, can be inhibited by CKI-7, an ATP-competitive inhibitor for the casein kinase 1. We have determined that CKI-7 is also a moderate inhibitor for the atypical APH(9)-Ia. Here we present the crystal structures of CKI-7-bound APH(3′)-IIIa and APH(9)-Ia, the first structures of a eukaryotic protein kinase inhibitor in complex with bacterial kinases. CKI-7 binds to the nucleotide-binding pocket of the enzymes and its binding alters the conformation of the nucleotide-binding loop, the segment homologous to the glycine-rich loop in eurkaryotic protein kinases. Comparison of these structures with the CKI-7-bound casein kinase 1 reveals features in the binding pockets that are distinct in the bacterial kinases and could be exploited for the design of a bacterial kinase specific inhibitor. Our results provide evidence that an inhibitor for a subset of APHs can be developed in order to curtail resistance to aminoglycosides.
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影响因子：
2.9
作者：
HIDAKA, H;INAGAKI, M;SASAKI, Y
通讯作者：
SASAKI, Y
影响因子：
13.5
作者：
Burk, DL;Berghuis, AM
通讯作者：
Berghuis, AM
影响因子：
4.8
作者：
MCKAY, GA;WRIGHT, GD
通讯作者：
WRIGHT, GD
DOI：
10.1107/s0907444909052925
发表时间：
2010-02
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Adams PD;Afonine PV;Bunkóczi G;Chen VB;Davis IW;Echols N;Headd JJ;Hung LW;Kapral GJ;Grosse-Kunstleve RW;McCoy AJ;Moriarty NW;Oeffner R;Read RJ;Richardson DC;Richardson JS;Terwilliger TC;Zwart PH
通讯作者：
Zwart PH
影响因子：
11.8
作者：
Boucher, Helen W.;Talbot, George H.;Bartlett, John
通讯作者：
Bartlett, John