Robertson Michael P, Igel Haller, Baertsch Robert, Haussler David, Ares Manuel, Scott William G
The Center for the Molecular Biology of RNA, University of California, Santa Cruz, USA.
PLoS Biol. 2005 Jan;3(1):e5. doi: 10.1371/journal.pbio.0030005. Epub 2004 Dec 28.
We have solved the three-dimensional crystal structure of the stem-loop II motif (s2m) RNA element of the SARS virus genome to 2.7-A resolution. SARS and related coronaviruses and astroviruses all possess a motif at the 3' end of their RNA genomes, called the s2m, whose pathogenic importance is inferred from its rigorous sequence conservation in an otherwise rapidly mutable RNA genome. We find that this extreme conservation is clearly explained by the requirement to form a highly structured RNA whose unique tertiary structure includes a sharp 90 degrees kink of the helix axis and several novel longer-range tertiary interactions. The tertiary base interactions create a tunnel that runs perpendicular to the main helical axis whose interior is negatively charged and binds two magnesium ions. These unusual features likely form interaction surfaces with conserved host cell components or other reactive sites required for virus function. Based on its conservation in viral pathogen genomes and its absence in the human genome, we suggest that these unusual structural features in the s2m RNA element are attractive targets for the design of anti-viral therapeutic agents. Structural genomics has sought to deduce protein function based on three-dimensional homology. Here we have extended this approach to RNA by proposing potential functions for a rigorously conserved set of RNA tertiary structural interactions that occur within the SARS RNA genome itself. Based on tertiary structural comparisons, we propose the s2m RNA binds one or more proteins possessing an oligomer-binding-like fold, and we suggest a possible mechanism for SARS viral RNA hijacking of host protein synthesis, both based upon observed s2m RNA macromolecular mimicry of a relevant ribosomal RNA fold.
我们已将严重急性呼吸综合征（SARS）病毒基因组的茎环II基序（s2m）RNA元件的三维晶体结构解析到2.7埃的分辨率。SARS及相关冠状病毒和星状病毒在其RNA基因组的3'端均拥有一个基序，称为s2m，鉴于其在原本快速变异的RNA基因组中严格的序列保守性，可推断其具有致病重要性。我们发现，这种极端的保守性可通过形成高度结构化RNA的需求得到清晰解释，该RNA独特的三级结构包括螺旋轴90度的急剧弯折以及几种新颖的长程三级相互作用。三级碱基相互作用形成了一条垂直于主螺旋轴的通道，其内部带负电荷并结合两个镁离子。这些不同寻常的特征可能与保守的宿主细胞成分或病毒功能所需的其他反应位点形成相互作用表面。基于其在病毒病原体基因组中的保守性以及在人类基因组中的缺失，我们认为s2m RNA元件中这些不同寻常的结构特征是抗病毒治疗药物设计的有吸引力的靶点。结构基因组学试图基于三维同源性推断蛋白质功能。在此，我们通过为SARS RNA基因组自身内一组严格保守的RNA三级结构相互作用提出潜在功能，将这种方法扩展到了RNA。基于三级结构比较，我们提出s2m RNA结合一种或多种具有类似寡聚物结合折叠的蛋白质，并基于观察到的s2m RNA对相关核糖体RNA折叠的大分子模拟，提出了SARS病毒RNA劫持宿主蛋白质合成的一种可能机制。
