HIV-1 uses dynamic capsid pores to import nucleotides and fuel encapsidated DNA synthesis.
HIV-1 uses dynamic capsid pores to import nucleotides and fuel encapsidated DNA synthesis.
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DOI：
10.1038/nature19098
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发表时间：
2016-08-18
期刊：
影响因子：
64.8
通讯作者：
James LC
中科院分区：
文献类型：
--
作者：
Jacques DA;McEwan WA;Hilditch L;Price AJ;Towers GJ;James LC
在感染的早期阶段，HIV-1衣壳保护病毒成分免受细胞质传感器（如cGAS）和核酸酶（如TREX）的攻击，同时允许获得核苷酸进行有效的反转录。在这里，我们展示了每个衣壳六聚体都有一个由六个精氨酸残基组成的环和一个由n端β-发夹形成的“分子虹膜”所包围的大小选择孔。精氨酸环产生一个带强正电的通道，以接近扩散极限的速率招募四个核苷酸。孔精氨酸的逐渐去除导致核苷酸亲和力、逆转录和感染性的剂量依赖性降低。这个带正电的通道在慢病毒衣壳中是普遍保守的，尽管它在没有核苷酸抵消电荷排斥的情况下是强烈不稳定的。我们还描述了一种通道抑制剂，hexacarboxybenzene，它与核苷酸结合竞争，并有效地阻断了被封装的逆转录，证明了孔作为一种新的药物靶点的可追溯性。
During the early stages of infection, the HIV-1 capsid protects viral components from cytosolic sensors, such as cGAS, and nucleases, such as TREX, while allowing access to nucleotides for efficient reverse transcription. Here we show that each capsid hexamer has a size-selective pore bounded by a ring of six arginine residues and a ‘molecular iris’ formed by the N-terminal β-hairpin. The arginine ring creates a strongly positively charged channel that recruits the four nucleotides with on-rates that near diffusion limits. Progressive removal of pore arginines results in a dose-dependent and concomitant decrease in nucleotide affinity, reverse transcription and infectivity. This positively charged channel is universally conserved in lentiviral capsids despite the fact that it is strongly destabilising without nucleotides to counteract charge repulsion. We also describe a channel inhibitor, hexacarboxybenzene, which competes for nucleotide binding and efficiently blocks encapsidated reverse transcription demonstrating the tractability of the pore as a novel drug target.