Multidisciplinary studies with mutated HIV-1 capsid proteins reveal structural mechanisms of lattice stabilization.
Multidisciplinary studies with mutated HIV-1 capsid proteins reveal structural mechanisms of lattice stabilization.
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DOI：
10.1038/s41467-023-41197-7
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发表时间：
2023-09-12
影响因子：
16.6
通讯作者：
Sarafianos SG
中科院分区：
文献类型：
--
作者：
Gres AT;Kirby KA;McFadden WM;Du H;Liu D;Xu C;Bryer AJ;Perilla JR;Shi J;Aiken C;Fu X;Zhang P;Francis AC;Melikyan GB;Sarafianos SG
HIV-1衣壳（CA）的稳定性对病毒复制很重要。E45 A和P38 A突变增强和降低核心稳定性，从而削弱感染性。第二位点突变R132 T和T216 I挽救了感染性。通过求解包括P38 A、P38 A/T216 I、E45 A、E45 A/R132 T CA在内的七种晶体结构（在天然背景下）来研究衣壳晶格稳定性，使用晶格的分子动力学模拟、组装体的冷冻电子显微镜、未包衣的时间分辨成像、组装体和稳定性的生物物理和生物化学表征。我们报告了明显和微妙的，短期和长期的重排：（1）A38不稳定的六聚体之间的相互作用松动的侧翼CA原聚体在P38 A，而不是P38 A/T216 I结构。(2)两个E45 A结构显示出意想不到的稳定化CANTD-CANTD六聚体间相互作用、可变的R18环孔径和翻转的N端β-发夹。(3)与WT、E45 A/R132 T、WTPF 74、WTNup 153和WTCPSF 6相比，E45 Aa α9-螺旋的构象改变降低了PF 74、CPSF 6和Nup 153的结合，并且在E45 A/R132 T中逆转。(4)E45和D51之间的环境敏感的静电排斥影响晶格稳定性，灵活性，离子和水的渗透性，静电，和主机因素的识别。E45 A或P38 A衣壳突变对HIV核心稳定性和感染性的影响可被R132 T或T216 I逆转。在这里，作者使用结构和生物物理方法来揭示解释稳定性变化的短程和长程重排。
HIV-1 capsid (CA) stability is important for viral replication. E45A and P38A mutations enhance and reduce core stability, thus impairing infectivity. Second-site mutations R132T and T216I rescue infectivity. Capsid lattice stability was studied by solving seven crystal structures (in native background), including P38A, P38A/T216I, E45A, E45A/R132T CA, using molecular dynamics simulations of lattices, cryo-electron microscopy of assemblies, time-resolved imaging of uncoating, biophysical and biochemical characterization of assembly and stability. We report pronounced and subtle, short- and long-range rearrangements: (1) A38 destabilized hexamers by loosening interactions between flanking CA protomers in P38A but not P38A/T216I structures. (2) Two E45A structures showed unexpected stabilizing CANTD-CANTD inter-hexamer interactions, variable R18-ring pore sizes, and flipped N-terminal β-hairpin. (3) Altered conformations of E45Aa α9-helices compared to WT, E45A/R132T, WTPF74, WTNup153, and WTCPSF6 decreased PF74, CPSF6, and Nup153 binding, and was reversed in E45A/R132T. (4) An environmentally sensitive electrostatic repulsion between E45 and D51 affected lattice stability, flexibility, ion and water permeabilities, electrostatics, and recognition of host factors. The effects of E45A or P38A capsid mutations on HIV core stability and infectivity are reversed by R132T or T216I. Here, authors used structural and biophysical methods to reveal short- and long-range rearrangements that explain stability changes.
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DOI：
10.1107/s0907444905036693
发表时间：
2006-01-01
影响因子：
2.2
作者：
Evans, P
通讯作者：
Evans, P
影响因子：
5.6
作者：
Datta, Siddhartha A. K.;Zhao, Zhuojun;Rein, Alan
通讯作者：
Rein, Alan
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
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通讯作者：
Cowtan, K
DOI：
10.1073/pnas.1419945112
发表时间：
2014-12-30
影响因子：
11.1
作者：
Bhattacharya, Akash;Alam, Steven L.;Yeager, Mark
通讯作者：
Yeager, Mark
影响因子：
5.4
作者：
Forshey, BM;Shi, J;Aiken, C
通讯作者：
Aiken, C