耐多药性HIV-1蛋白酶的开放结构是通过结晶包装接触点来稳定
Melinda Layten1, Viktor Hornak, Carlos Simmerling
1Program in Molecular and Cellular Biology, Department of Chemistry, and Center for Structural Biology, Stony Brook University, Stony Brook, NY 11794, USA.
Journal of the American Chemical Society
|October 13, 2006
概括
在HIV-1蛋白酶 (HIV-PR) 中出现的耐药性威胁到患者的生存. 模拟显示,最近报告的一种耐药HIV-PR突变体的开放晶体结构是不稳定的,可能是一种人工制造物,不解释耐药机制.
科学领域:
- 生物化学 生物化学
- 结构生物学 结构生物学
- 计算生物学 计算生物学
背景情况:
- 艾滋病毒-1蛋白酶 (HIV-PR) 抑制剂改善了患者的存活率,但面临着耐药菌株的挑战.
- 了解HIV-PR的动态和耐药性突变对于设计新的抑制剂至关重要.
研究的目的:
- 为了研究多药耐药 (MDR) 769 个HIV-PR突变体的结构动态.
- 评估最近报告的MDR 769 HIV-PR的开放晶体结构 (PDB:1TW7) 与药物耐药性的相关性.
主要方法:
- 对MDR 769HIV-PR突变体的分子动力学模拟.
- 在溶液中分析蛋白酶结构动力学.
主要成果:
- 报告的MDR 769 HIV-PR的开放晶体结构在溶液中不稳定,迅速采用类似于野生类型无结合蛋白酶的半开放形状.
- 在MDR 769晶体结构中观察到的开放状态可能是晶体包装的工件,而不是序列变化.
- 这种结构可能不能准确地代表抑制剂的进入或HIV-PR药物耐药性的原因.
结论:
- 在MDR 769晶体结构中观察到的开放结合口袋并不代表蛋白酶在溶液中的行为.
- 在MDR 769分离物中耐药性的原因可能与抑制剂无法诱导关闭直接相关,正如这种晶体结构所暗示的那样.
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