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Escape from inhibition

机译：摆脱束缚

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摘要

Mutations in the Abl protein cause some leukaemias. The determination of its structure and the identification of Abl variants resistant to an anti-leukaemia drug reveal regions of the protein needed for its regulation. The enigmatic protein Abl has just given up another of its secrets. This enzyme is important because in mutated, activated form it causes some types of human leukaemia―so researchers have been keen to learn how it is regulated. That goal became still more precious when it was realized that the resistance of leukaemia to Gleevec (a drug that inhibits Abl) often results from further mutations in Abl itself. But until now the protein has stubbornly resisted attempts to understand it. Writing in Cell, however, Hantschel and colleagues and Nagar and co-workers describe how they used a combination of mutational and crystallographic analyses to solve the puzzle. In a surprising twist, the regulation of Abl turns out to closely resemble that of a related enzyme, Src, despite key structural differences. Meanwhile, a complementary paper by Azam and colleagues in the same issue describes the use of an in vitro assay to screen for Gleevec-resistant variants of Abl. This work reveals that Abl can escape Gleevec inhibition by mutating several amino acids now shown to be key to its regulation. Together these findings have implications for the design of the next generation of Abl inhibitors, and provide an unbiased assay with which drug resistance in Abl can be probed in the future.
机译：Abl蛋白的突变会导致某些白血病。其结构的确定和对一种抗白血病药物具有抗性的Abl变体的鉴定揭示了其调节所需的蛋白质区域。神秘的蛋白质Abl刚刚放弃了另一个秘密。这种酶很重要，因为它以突变，活化的形式引起某些类型的人类白血病-因此研究人员一直热衷于了解其调控方式。当人们意识到白血病对格列卫（一种抑制Abl的药物）的耐药性通常是由Abl本身的进一步突变导致的时，这一目标变得更加珍贵。但是直到现在，这种蛋白质仍顽固地抵抗了试图理解它的尝试。然而，汉斯切尔（Hantschel）及其同事，纳加尔（Nagar）及其同事在《细胞》杂志上写道，他们如何结合使用突变和晶体学分析来解决这一难题。出乎意料的是，尽管存在关键的结构差异，但Abl的调控却与相关酶Src的调控极为相似。同时，Azam和他的同事在同一期的一篇补充论文中描述了使用体外测定法筛选抗Gleevec的Abl变异体的方法。这项工作表明，Abl可以通过突变目前证明对其调节至关重要的几种氨基酸来逃避格列卫的抑制作用。这些发现共同影响了下一代Abl抑制剂的设计，并提供了一种可用于将来检测Abl耐药性的无偏分析方法。

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  • 来源
    《Nature》 |2003年第6934期|p.827-828|共2页
  • 作者

    Sara A. Courtneidge;

  • 作者单位

    Van Andel Research Institute, 333 Bostwick Avenue NE, Grand Rapids, Michigan 49503, USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 自然科学总论;
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