Definition of the binding mode of a new class of phosphoinositide 3-kinase α-selective inhibitors using in vitro mutagenesis of non-conserved amino acids and kinetic analysis.
Definition of the binding mode of a new class of phosphoinositide 3-kinase α-selective inhibitors using in vitro mutagenesis of non-conserved amino acids and kinetic analysis.
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DOI：
10.1042/bj20120499
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发表时间：
2012-06-15
期刊：
影响因子：
--
通讯作者：
Jennings IG
中科院分区：
文献类型：
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作者：
Zheng Z;Amran SI;Zhu J;Schmidt-Kittler O;Kinzler KW;Vogelstein B;Shepherd PR;Thompson PE;Jennings IG
一类新型脂质竞争性、ATP 非竞争性、p110α 亚型选择性 PI3K（磷酸肌醇 3 激酶）抑制剂的结合机制已被阐明。利用 p110α 和 p110β 亚型中非保守氨基酸的亚型相互诱变新技术，我们确定了 p110α 选择性抑制剂 PIK-75、A-66S 和 J-32 的三种独特的结合机制。每种抑制剂的 p110α-亚型选择性结合被发现是由于与 p110 内不同氨基酸的相互作用。 PIK-75 相互作用结合非保守区域 2 氨基酸 p110α Ser773，A-66S 结合区域 1 非保守氨基酸 p110α Gln859，J-32 结合与 Lys776 和 Ile771 具有间接相互作用。异构体相互诱变技术被证明是合理设计异构体选择性抑制剂的重要分析工具。
The binding mechanism of a new class of lipid-competitive, ATP non-competitive, p110α isoform-selective PI3K (phosphoinositide 3-kinase) inhibitors has been elucidated. Using the novel technique of isoform reciprocal mutagenesis of non-conserved amino acids in the p110α and p110β isoforms, we have identified three unique binding mechanisms for the p110α-selective inhibitors PIK-75, A-66S and J-32. Each of the inhibitor’s p110α-isoform-selective binding was found to be due to interactions with different amino acids within p110. The PIK-75 interaction bound the non-conserved region 2 amino acid p110α Ser773, A-66S bound the region 1 non-conserved amino acid p110α Gln859, and J-32 binding had an indirect interaction with Lys776 and Ile771. The isoform reciprocal mutagenesis technique is shown to be an important analytical tool for the rational design of isoform-selective inhibitors.