2012年11月14日 訊 /生物谷BIOON/ --近日,，佛羅里達州斯克里普斯研究所（TSRI的科學(xué)家確定了一種酶的分子結(jié)構(gòu)，該酶與幾種蛋白質(zhì)相互作用參與影響神經(jīng)退行性疾病與胰島素抵抗過程,。這種酶在神經(jīng)細胞（神經(jīng)元）的生存中起到了關(guān)鍵作用,，是一個治療大腦疾病如帕金森氏癥,，阿爾茨海默氏癥和肌萎縮性脊髓側(cè)索硬化癥（ALS）的潛在藥物靶標。
這項研究發(fā)表在2012年11月8日的Structure雜志上,。這項新的研究揭示了一類稱為JNK的激酶,，當綁定到不同蛋白質(zhì)家族的三肽酶結(jié)構(gòu)時，JNK是應(yīng)激誘導(dǎo)的細胞凋亡（細胞死亡）的一個重要因素,。在動物模型中的研究表明,，抑制JNK對神經(jīng)退行性疾病具有保護作用。
Philip LoGrasso教授說：我們的研究結(jié)果有助于開發(fā)靶向JNK的藥物,。了解JNK綁定到這些蛋白質(zhì)的結(jié)構(gòu)將使我們能夠開發(fā)出這種酶的特異競爭性抑制劑,。從結(jié)構(gòu)上看，JNK結(jié)合的這些不同的蛋白質(zhì)非常相似,，但生物化學(xué)研究表明,，他們結(jié)合JNK后所帶來的作用有很大不同。 LoGrasso和他的同事們負責利用X-射線晶體學(xué)創(chuàng)建和解決三肽（JIP1,，SAB,，和ATF-2）的晶體結(jié)構(gòu)，而Nettles研究員進行數(shù)據(jù)分析處理,。
LoGrasso說,，解決JNK這三個結(jié)合肽的晶體結(jié)構(gòu)，為我們提供了一個清晰的概念,，讓我們能了解如何能利用每一個確切的分子機制來阻止細胞死亡和生存,。（生物谷Bioon.com）
doi:10.1016/j.str.2012.09.021
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PMID:
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.
