对于艾滋病毒来说,指向下:在NNRTI结合的HIV-1逆转录酶中确实发生了域级重组
David W Wright1, S Kashif Sadiq, Gianni De Fabritiis
1Centre for Computational Science, Department of Chemistry, University College London , London WC1H 0AJ, U.K.
Journal of the American Chemical Society
|July 26, 2012
概括
非核类逆转录酶抑制剂 (NNRTIs) 在开放状态下不能完全锁定HIV-1 RT. 模拟显示,与药物结合的酶存在于开放和闭合形状的分布中,改变了过渡动力学.
科学领域:
- 生物化学 生物化学
- 结构生物学 结构生物学
- 药物发现 药物发现 药物发现
背景情况:
- 人类免疫缺陷病毒1型 (HIV-1) 逆转录酶 (RT) 是一个关键的治疗点.
- 非核酸RT抑制剂 (NNRTIs) 通过结合到活性部位附近的口袋,以全质抑制HIV-1RT.
- 目前的模型建议NNRTIs作为分子子,迫使酶进入永久开放的构造.
研究的目的:
- 为了研究HIV-1RT与NNRTI efavirenz结合时的构造动态.
- 挑战NNRTI抑制的既定"分子"模型.
- 阐明NNRTI对RT形态状态的作用的全性机制.
主要方法:
- 采用了整体分子动力学模拟.
- 模拟总计约600纳秒的采样时间.
- 分析了与埃法维伦兹结合的RT的构造状态.
主要成果:
- 模拟捕获了与efavirenz结合的HIV-1RT在一个封闭的构造中,类似于apo酶.
- 这表明NNRTI绑定并不能完全限制指域运动.
- 在药物结合酶中存在开放和闭合状态之间的构造分布.
结论:
- 通过NNRTIs进行的体调制是通过改变构造转换的动力学来发生的.
- "分子"假说可能过度简化了NRTI抑制机制.
- 了解这些动态可以指导改进的HIV-1抑制剂和新型全位的设计.
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