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PNAS:HIV-1衣壳分解分子机制 助力艾滋病新型疗法开发

来源:生物谷 2015-01-04 10:36

2015年1月4日 讯 /生物谷BIOON/ --试想当一个行李箱在颠簸的旅途被碰开时,箱子中整理的衣服会洒落一地;而类似尴尬的事情就好比是你的手提箱在该打开的时候死活打不开。上述比喻说明了HIV-1衣壳对于HIV-1的重要性,衣壳是保护HIV-1的保护性“胶囊”,一旦病毒进入机体细胞中其必须分解,在合适的地点和合适的时间释放出病毒核酸。

近日,发表在国际杂志PNAS上的一篇研究论文中,来自美国德克萨斯大学健康科学中心的研究人员通过研究表示,至今科学界关于HIV-1病毒衣壳在感染细胞中什么情况下会分解依然存在争议,而本文研究中我们就揭示了一种名为PF74的HIV-1抑制剂以及宿主蛋白CPSF6如何同病毒衣壳表面的小槽相结合来抑制衣壳的分解,进而抑制病毒的感染和传播。

Ivanov博士说道,我们认为清晰地解析该过程或可帮助开发治疗HIV-1感染的新型靶向疗法,文章中利用X射线晶体学技术我们清楚地观察了结合HIV-1衣壳的蛋白质CPSF6的三维结构。

清楚地观察CPSF6蛋白的3D结构对于我们理解HIV-1的感染过程非常关键,如今我们揭示了PF74和CPSF6蛋白同HIV衣壳相结合阻断衣壳分解的分子机制,而后期我们也将开发出可以结合HIV衣壳的新型分子,从而来抑制HIV-1在细胞中的复制以及感染。(生物谷Bioon.com)

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Structural basis of HIV-1 capsid recognition by PF74 and CPSF6

Akash Bhattacharyaa, Steven L. Alamb, Thomas Frickec, Kaneil Zadroznyd, Jaroslaw Sedzickid, Alexander B. Taylora, Borries Demelera, Owen Pornillosd,e, Barbie K. Ganser-Pornillosd, Felipe Diaz-Grifferoc, Dmitri N. Ivanova,1, and Mark Yeagerd,e,f,g,1

Upon infection of susceptible cells by HIV-1, the conical capsid formed by ∼250 hexamers and 12 pentamers of the CA protein is delivered to the cytoplasm. The capsid shields the RNA genome and proteins required for reverse transcription. In addition, the surface of the capsid mediates numerous host–virus interactions, which either promote infection or enable viral restriction by innate immune responses. In the intact capsid, there is an intermolecular interface between the N-terminal domain (NTD) of one subunit and the C-terminal domain (CTD) of the adjacent subunit within the same hexameric ring. The NTD–CTD interface is critical for capsid assembly, both as an architectural element of the CA hexamer and pentamer and as a mechanistic element for generating lattice curvature. Here we report biochemical experiments showing that PF-3450074 (PF74), a drug that inhibits HIV-1 infection, as well as host proteins cleavage and polyadenylation specific factor 6 (CPSF6) and nucleoporin 153 kDa (NUP153), bind to the CA hexamer with at least 10-fold higher affinities compared with nonassembled CA or isolated CA domains. The crystal structure of PF74 in complex with the CA hexamer reveals that PF74 binds in a preformed pocket encompassing the NTD–CTD interface, suggesting that the principal inhibitory target of PF74 is the assembled capsid. Likewise, CPSF6 binds in the same pocket. Given that the NTD–CTD interface is a specific molecular signature of assembled hexamers in the capsid, binding of NUP153 at this site suggests that key features of capsid architecture remain intact upon delivery of the preintegration complex to the nucleus.

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