Key Laboratory of Special Pathogens and Biosafety, Center for Biosafety Mega-Science, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, Hubei 430071, China.
University of Chinese Academy of Sciences, Beijing 100049, China.
Proc Natl Acad Sci U S A. 2023 Jan 3;120(1):e2211425120. doi: 10.1073/pnas.2211425120. Epub 2022 Dec 28.
De novo viral RNA-dependent RNA polymerases (RdRPs) utilize their priming element (PE) to facilitate accurate initiation. Upon transition to elongation, the PE has to retreat from the active site to give room to the template-product RNA duplex. However, PE conformational change upon this transition and the role of PE at elongation both remain elusive. Here, we report crystal structures of RdRP elongation complex (EC) from dengue virus serotype 2 (DENV2), demonstrating a dramatic refolding of PE that allows establishment of interactions with the RNA duplex backbone approved to be essential for EC stability. Enzymology data from both DENV2 and hepatitis C virus (HCV) RdRPs suggest that critical transition of the refolding likely occurs after synthesis of a 4- to 5-nucleotide (nt) product together providing a key basis in understanding viral RdRP transition from initiation to elongation.
从头病毒 RNA 依赖性 RNA 聚合酶（RdRPs）利用其启动元件（PE）来促进准确的起始。在过渡到延伸阶段时，PE 必须从活性位点后退，为模板-产物 RNA 双链腾出空间。然而，PE 在这种转变过程中的构象变化以及 PE 在延伸阶段的作用仍然难以捉摸。在这里，我们报告了登革热病毒 2 型（DENV2）RdRP 延伸复合物（EC）的晶体结构，该结构展示了 PE 的剧烈重折叠，允许与 RNA 双链骨架建立相互作用，这些相互作用被证明对于 EC 的稳定性至关重要。来自 DENV2 和丙型肝炎病毒（HCV）RdRPs 的酶学数据表明，重折叠的关键转变可能发生在合成 4-5 个核苷酸（nt）产物之后，这为理解病毒 RdRP 从起始到延伸的转变提供了关键依据。
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