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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >MS3D structural elucidation of the HIV-1 packaging signal
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MS3D structural elucidation of the HIV-1 packaging signal

机译：MS3D对HIV-1包装信号的结构解析

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摘要

The structure of HIV-1 Ψ-RNA has been elucidated by a concerted approach combining structural probes with mass spectrometric detection (MS3D), which is not affected by the size and crystallization properties of target biomolecules. Distance constraints from bifunctional cross-linkers provided the information required for assembling an all-atom model from the high-resolution coordinates of separate domains by triangulating their reciprocal placement in 3D space. The resulting structure revealed a compact cloverleaf morphology stabilized by a long-range tertiary interaction between the GNRA tetraloop of stemloop 4 (SL4) and the upper stem of stemloop 1 (SL1), The preservation of discrete stemloop structures ruled out the possibility that major rearrangements might produce a putative supersite with enhanced affinity for the nucleocapsid (NC) domain of the viral Gag polyprotein, which would drive genome recognition and packaging. The steric situation of single-stranded regions exposed on the cloverleaf structure offered a valid explanation for the stoichiometry exhibited by full-length Ψ-RNA in the presence of NC. The participation of SL4 in a putative GNRA loop-receptor interaction provided further indications of the plasticity of this region of genomic RNA, which can also anneal with upstream sequences to stabilize alternative conformations of the 5' untranslated region (5-UTR). Considering the ability to sustain specific NC binding, the multifaceted activities supported by the SL4 sequence suggest a mechanism by which Gag could actively participate in regulating the vital functions mediated by S'-UTR. Substantiated by the 3D structure of Ψ-RNA, the central role played by SL4 in specific RNA-RNA and protein-RNA interactions advances this domain as a primary target for possible therapeutic intervention.
机译：通过将结构探针与质谱检测（MS3D）结合使用的协同方法已经阐明了HIV-1β-RNA的结构，该方法不受目标生物分子的大小和结晶特性的影响。来自双功能交联剂的距离限制通过三角测量它们在3D空间中的相互位置，提供了从各个域的高分辨率坐标组装全原子模型所需的信息。最终的结构揭示了紧密的苜蓿叶形态，其通过茎环4（SL4）的GNRA四环和茎环1（SL1）的上部茎之间的长距离三级相互作用而得以稳定。离散茎环结构的保留排除了重大重排的可能性可能产生对病毒Gag多蛋白的核衣壳（NC）结构域具有增强亲和力的推定超位点，这将推动基因组识别和包装。苜蓿叶形结构上暴露的单链区域的空间状态为全长Ψ-RNA在NC存在下显示的化学计量提供了有效的解释。 SL4参与公认的GNRA环-受体相互作用提供了该基因组RNA区域可塑性的进一步指示，这也可以与上游序列退火以稳定5'非翻译区（5-UTR）的替代构象。考虑到维持特定NC结合的能力，SL4序列支持的多方面活动提示Gag可以积极参与调节S'-UTR介导的重要功能的机制。由Ψ-RNA的3D结构证实，SL4在特定RNA-RNA和蛋白质-RNA相互作用中发挥的核心作用使该结构域成为可能的治疗干预的主要靶标。

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