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Updated: Jun 5, 2025

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艾滋病毒-1包膜三元体从预注射关闭过渡到CD4结合的开放形状,通过一个封闭的中间状态

Myungjin Lee¹, Maolin Lu², Baoshan Zhang¹

¹Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.

Computational and structural biotechnology journal

|December 6, 2024

概括

研究人员使用分子动力学和smFRET探索了HIV-1包膜 (Env) 缩剂的动态转换. 他们发现了一种由抗体识别的新型"封闭-中间"状态,这对于理解病毒进入和中和至关重要.

科学领域:

结构生物学结构生物学
病毒学病毒学
生物物理学的生物物理.

背景情况:

艾滋病毒-1感染始于包膜 (Env) 三分离体与宿主细胞受体CD4结合,导致显著的结构变化.
Env trimers的静态结构存在,但这些状态之间的动态过渡,特别是中间阶段,是不太了解的.
了解这些动态对于开发有效的HIV-1治疗方法至关重要.

研究的目的:

为了研究一个糖基化HIV-1 Env缩剂从其封闭到CD4结合的开放形状的完整过渡途径.
在这种形状变化过程中识别和描述动态中间状态.
探索抗体与这些中间状态的相互作用.

主要方法:

采用集体分子动力学模拟来建模Envtrimer的结构变化.
利用单分子弗斯特共振能量转移 (smFRET) 来实验观察和验证过渡途径.
分析了结构重组,包括可变循环运动和二次结构变化.

主要成果:

揭示了Env三元体过渡途径的关键特征,例如甘氨酸孔的形成和α螺旋和β链的改变.
在Envtrimer的过渡过程中确定了以前未经描述的"封闭中介"状态.
证明了四种特定抗体 (Ab1303,Ab1573,b12,DH851.3) 结合并稳定这种封闭的中间状态,改变了Env种群.

结论:

封闭式中间状态代表了HIV-1 Env trimer的流行和中和相关的构造.
这种状态存在于前封闭和CD4结合的开放形状之间,以前在smFRET分析中被忽视了.
了解这种中间状态及其与抗体的相互作用为HIV-1疫苗和药物设计提供了新的目标.

关键词:

抗体识别对抗体的识别这种CD4受体是CD4受体.艾滋病毒-1 Envv 分子动力学分子动力学这是一个smFRETET.

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