Department of Chemistry, University of Washington, Seattle, Washington 98195-1700, USA.
RNA. 2022 Sep;28(9):1210-1223. doi: 10.1261/rna.079197.122. Epub 2022 Jun 24.
Dengue virus, a single-stranded positive sense RNA virus, is the most prevalent mosquito-borne pathogen in the world. Like all RNA viruses, it uses conserved structural elements within its genome to control essential replicative steps. A 70 nt stem-loop RNA structure (called SLA), found at the 5'-end of the genome of all flaviviruses, functions as the promoter for viral replication. This highly conserved structure interacts with the viral polymerase NS5 to initiate RNA synthesis. Here, we report the NMR structure of a monomeric SLA from dengue virus serotype 1, assembled to high-resolution from independently folded structural elements. The DENV1 SLA has an L-shaped structure, where the top and side helices are coaxially stacked, and the bottom helix is roughly perpendicular to them. Because the sequence is highly conserved among different flavivirus genomes, it is very likely that the three-dimensional fold and local structure of SLA are also conserved among flaviviruses and required for efficient replication. This work provides structural insight into the dengue promoter and provides the foundation for the discovery of new antiviral drugs that target this essential replicative step.
登革热病毒是一种单链正链 RNA 病毒，是世界上最普遍的蚊媒病原体。与所有 RNA 病毒一样，它利用基因组内保守的结构元件来控制关键的复制步骤。在所有黄病毒基因组的 5' 端，存在一个 70 个核苷酸的茎环 RNA 结构（称为 SLA），它作为病毒复制的启动子。这种高度保守的结构与病毒聚合酶 NS5 相互作用，启动 RNA 合成。在这里，我们报告了来自登革热病毒血清型 1 的单体 SLA 的 NMR 结构，该结构由独立折叠的结构元件组装而成，分辨率很高。DENV1 SLA 具有 L 形结构，其中顶部和侧面螺旋同轴堆叠，底部螺旋大致垂直于它们。由于序列在不同的黄病毒基因组中高度保守，因此 SLA 的三维折叠和局部结构很可能在黄病毒中也是保守的，并且对于有效的复制是必需的。这项工作为登革热启动子提供了结构见解，并为发现针对这一关键复制步骤的新型抗病毒药物提供了基础。
