2012年11月14日 讯 /生物谷BIOON/ --近日,佛罗里达州斯克里普斯研究所(TSRI的科学家确定了一种酶的分子结构,该酶与几种蛋白质相互作用参与影响神经退行性疾病与胰岛素抵抗过程。这种酶在神经细胞(神经元)的生存中起到了关键作用,是一个治疗大脑疾病如帕金森氏症,阿尔茨海默氏症和肌萎缩性脊髓侧索硬化症(ALS)的潜在药物靶标。
这项研究发表在2012年11月8日的Structure杂志上。这项新的研究揭示了一类称为JNK的激酶,当绑定到不同蛋白质家族的三肽酶结构时,JNK是应激诱导的细胞凋亡(细胞死亡)的一个重要因素。在动物模型中的研究表明,抑制JNK对神经退行性疾病具有保护作用。
Philip LoGrasso教授说:我们的研究结果有助于开发靶向JNK的药物。了解JNK绑定到这些蛋白质的结构将使我们能够开发出这种酶的特异竞争性抑制剂。从结构上看,JNK结合的这些不同的蛋白质非常相似,但生物化学研究表明,他们结合JNK后所带来的作用有很大不同。 LoGrasso和他的同事们负责利用X-射线晶体学创建和解决三肽(JIP1,SAB,和ATF-2)的晶体结构,而Nettles研究员进行数据分析处理。
LoGrasso说,解决JNK这三个结合肽的晶体结构,为我们提供了一个清晰的概念,让我们能了解如何能利用每一个确切的分子机制来阻止细胞死亡和生存。(生物谷Bioon.com)
doi:10.1016/j.str.2012.09.021
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Structural Mechanisms of Allostery and Autoinhibition in JNK Family Kinases
Laughlin JD, Nwachukwu JC, Figuera-Losada M, Cherry L, Nettles KW, Lograsso PV.
c-Jun N-terminal (JNK) family kinases have a common peptide-docking site used by upstream activating kinases, substrates, scaffold proteins, and phosphatases, where the ensemble of bound proteins determines signaling output. Although there are many JNK structures, little is known about mechanisms of allosteric regulation between the catalytic and peptide-binding sites, and the activation loop, whose phosphorylation is required for catalytic activity. Here, we compare three structures of unliganded JNK3 bound to different peptides. These were compared as a class to structures that differ in binding of peptide, small molecule ligand, or conformation of the kinase activation loop. Peptide binding induced an inhibitory interlobe conformer that was reversed by alterations in the activation loop. Structure class analysis revealed the subtle structural mechanisms for allosteric signaling between the peptide-binding site and activation loop. Biochemical data from isothermal calorimetry, fluorescence energy transfer, and enzyme inhibition demonstrated affinity differences among the three peptides that were consistent with structural observations.