Structural dynamics reveal isolate-specific differences at neutralization epitopes on HIV Env.
Structural dynamics reveal isolate-specific differences at neutralization epitopes on HIV Env.
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结构动力学揭示了HIV Env中和表位的分离特异性差异。
DOI：
10.1016/j.isci.2022.104449
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发表时间：
2022-06-17
期刊：
影响因子：
5.8
通讯作者：
Lee, Kelly K.
中科院分区：
文献类型：
--
作者：
Hodge, Edgar A.;Naika, Gajendra S.;Kephart, Sally M.;Nguyen, Adam;Zhu, Richard;Benhaim, Mark A.;Guo, Wenjin;Moore, John P.;Hu, Shiu-Lok;Sanders, Rogier W.;Lee, Kelly K.
包膜糖蛋白（Env）是中和抗HIV抗体的唯一靶标，也是病毒中进化最快的可变部分。在融合前捕获的Env三聚体的高分辨率结构，封闭构象揭示了不同分离株之间高度的结构相似性。然而，生物物理数据表明，Env是高度动态的，并且动力学和构象采样的水平被认为在不同的HIV分离株之间差异很大。动态差异可能影响中和敏感性、受体激活和整体三聚体稳定性。在这里，使用氢/氘交换质谱（HDX-MS），我们绘制了来自不同分离株的原生类Env SOSIP三聚体的局部动态图。我们表明，在表位顺序的显著差异被广泛中和抗体靶向的大多数位点观察到。我们还观察到在广泛的时间尺度范围内发生的孤立依赖的构象切换。最后，我们报告了抑制某些分离株动力学的超稳定突变对其他分离株几乎没有影响。结构动力学是病毒抗原表型的重要决定因素H/ d交换质谱法揭示HIV Env三聚体的分离特异性变异HIV Env三聚体在广泛变化的时间尺度上表现出局部构象开关稳定突变猝灭Env动力学具有高度的分离依赖性；微生物学;结构生物学
The envelope glycoprotein (Env) is the sole target for neutralizing antibodies against HIV and the most rapidly evolving, variable part of the virus. High-resolution structures of Env trimers captured in the pre-fusion, closed conformation have revealed a high degree of structural similarity across diverse isolates. Biophysical data, however, indicate that Env is highly dynamic, and the level of dynamics and conformational sampling is believed to vary dramatically between HIV isolates. Dynamic differences likely influence neutralization sensitivity, receptor activation, and overall trimer stability. Here, using hydrogen/deuterium-exchange mass spectrometry (HDX-MS), we have mapped local dynamics across native-like Env SOSIP trimers from diverse isolates. We show that significant differences in epitope order are observed across most sites targeted by broadly neutralizing antibodies. We also observe isolate-dependent conformational switching that occurs over a broad range of timescales. Lastly, we report that hyper-stabilizing mutations that dampen dynamics in some isolates have little effect on others. Structural dynamics are an important determinant of viral antigenic phenotype H/D-exchange mass spectrometry reveals isolate-specific variation in HIV Env trimers HIV Env trimer exhibits local conformational switching on widely varying time scales Stabilizing mutations that quench Env dynamics have highly isolate-dependent effects Immunology; Microbiology; Structural biology
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影响因子：
8.8
作者：
Torrents de la Peña A;Julien JP;de Taeye SW;Garces F;Guttman M;Ozorowski G;Pritchard LK;Behrens AJ;Go EP;Burger JA;Schermer EE;Sliepen K;Ketas TJ;Pugach P;Yasmeen A;Cottrell CA;Torres JL;Vavourakis CD;van Gils MJ;LaBranche C;Montefiori DC;Desaire H;Crispin M;Klasse PJ;Lee KK;Moore JP;Ward AB;Wilson IA;Sanders RW
通讯作者：
Sanders RW
影响因子：
7.7
作者：
Hraber P;Korber B;Wagh K;Montefiori D;Roederer M
通讯作者：
Roederer M
影响因子：
16.6
作者：
Ananthaswamy, Neeti;Fang, Qianglin;Rao, Venigalla B.
通讯作者：
Rao, Venigalla B.
影响因子：
16.6
作者：
Han, Qifeng;Jones, Julia A.;Saunders, Kevin O.
通讯作者：
Saunders, Kevin O.
影响因子：
64.5
作者：
de Taeye SW;Ozorowski G;Torrents de la Peña A;Guttman M;Julien JP;van den Kerkhof TL;Burger JA;Pritchard LK;Pugach P;Yasmeen A;Crampton J;Hu J;Bontjer I;Torres JL;Arendt H;DeStefano J;Koff WC;Schuitemaker H;Eggink D;Berkhout B;Dean H;LaBranche C;Crotty S;Crispin M;Montefiori DC;Klasse PJ;Lee KK;Moore JP;Wilson IA;Ward AB;Sanders RW
通讯作者：
Sanders RW