High-Resolution Structure of the Nuclease Domain of the Human Parvovirus B19 Main Replication Protein NS1
High-Resolution Structure of the Nuclease Domain of the Human Parvovirus B19 Main Replication Protein NS1
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DOI：
10.1128/jvi.02164-21
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发表时间：
2021-12
影响因子：
5.4
通讯作者：
Jonathan L. Sanchez;N. Ghadirian;N. Horton
中科院分区：
文献类型：
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作者：
Jonathan L. Sanchez;N. Ghadirian;N. Horton
高分辨率结构的DNA结合和切割结构域的主要复制蛋白，NS 1，从人类致病性病毒人类细小病毒B19。还包括蛋白质如何识别病毒复制所需的病毒DNA中的重要序列的预测。本文报道了人细小病毒B19（B19 V）主要复制蛋白NS 1 N端结构域的两个新结构。该结构域（NS 1-nuc）在单链B19 V DNA基因组的“滚动发夹”复制中起重要作用，识别双链DNA中的复制起点序列，并切割（即，切口）单链DNA在附近的称为末端解析位点（trs）的位点处。NS 1-nuc的三维结构在两种形式之间以及与先前解决的相同结构域的序列变体的结构之间是很保守的;然而，它在这里以显著更高的分辨率（2.4 μ m）显示。使用结构的NS 1-nuc同系物绑定到单链和双链DNA，模型的DNA识别和切口B19 V NS 1-nuc的预测残基重要的DNA切割和序列特异性识别的病毒复制起点。重要性本文展示了人类致病性病毒人类细小病毒B19的主要复制蛋白NS 1的DNA结合和切割结构域的高分辨率结构。还包括蛋白质如何识别病毒复制所需的病毒DNA中的重要序列的预测。这些预测可用于进一步研究该蛋白的功能，以及预测由于病毒蛋白和病毒DNA序列中的突变对病毒存活力的影响。最后，高分辨率结构有助于结构指导的药物设计工作，以开发针对这种重要的人类病原体的抗病毒化合物。
The high-resolution structure of the DNA binding and cleavage domain of the main replicative protein, NS1, from the human-pathogenic virus human parvovirus B19 is presented here. Included also are predictions of how the protein recognizes important sequences in the viral DNA which are required for viral replication. ABSTRACT Two new structures of the N-terminal domain of the main replication protein, NS1, of human parvovirus B19 (B19V) are presented here. This domain (NS1-nuc) plays an important role in the “rolling hairpin” replication of the single-stranded B19V DNA genome, recognizing origin of replication sequences in double-stranded DNA, and cleaving (i.e., nicking) single-stranded DNA at a nearby site known as the terminal resolution site (trs). The three-dimensional structure of NS1-nuc is well conserved between the two forms, as well as with a previously solved structure of a sequence variant of the same domain; however, it is shown here at a significantly higher resolution (2.4 Å). Using structures of NS1-nuc homologues bound to single- and double-stranded DNA, models for DNA recognition and nicking by B19V NS1-nuc are presented that predict residues important for DNA cleavage and for sequence-specific recognition at the viral origin of replication. IMPORTANCE The high-resolution structure of the DNA binding and cleavage domain of the main replicative protein, NS1, from the human-pathogenic virus human parvovirus B19 is presented here. Included also are predictions of how the protein recognizes important sequences in the viral DNA which are required for viral replication. These predictions can be used to further investigate the function of this protein, as well as to predict the effects on viral viability due to mutations in the viral protein and viral DNA sequences. Finally, the high-resolution structure facilitates structure-guided drug design efforts to develop antiviral compounds against this important human pathogen.