Conserved Structural Motif Identified in Peptides That Bind to Geminivirus Replication Protein Rep,Biochemistry

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Conserved Structural Motif Identified in Peptides That Bind to Geminivirus Replication Protein Rep
Biochemistry ( IF 2.9 ) Pub Date : 2021-08-31 , DOI: 10.1021/acs.biochem.1c00408
J Trinidad Ascencio-Ibáñez ₁ , Benjamin G Bobay _{2,

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Affiliation

The geminivirus replication protein, Rep, has long been recognized as a high-value target for control of geminivirus infections as this protein is highly conserved and essential for viral replication and proliferation. In addition, inhibition of viral replication has been pursued through various antiviral strategies with varying degrees of success, including inhibitory peptides that target Rep. While much effort has centered around sequence characterization of the Rep protein and inhibitory peptides, detailed structural analysis has been missing. This study computationally investigated the presence of common structural features within these inhibitory peptides and if these features could inform if a particular peptide will bind Rep and/or interfere with viral replication. Molecular dynamics simulations of the inhibitory peptide library showed that simply possessing stable structural features does not inform interference of viral replication regardless of the binding of Rep. Additionally, nearly all known Rep inhibitory peptides sample a conserved β-sheet structural motif, possibly informing structure–function relationships in binding Rep. In particular, two peptides (A22 and A64) characterized by this structural motif were computationally docked against a wide variety of geminivirus Rep proteins to determine a mechanism of action. Computational docking revealed these peptides utilize a common Rep protein sequence motif for binding, HHN-x_1/2-Q. The results identified residues in both Rep and the inhibitory peptides that play a significant role in the interaction, establishing the foundation for a rational structure-based design approach for the construction of both broadly reactive and geminivirus species-specific inhibitors.

中文翻译：

在与双粒病毒复制蛋白 Rep 结合的肽中鉴定出保守的结构基序

双生病毒复制蛋白 Rep 长期以来一直被认为是控制双生病毒感染的高价值靶点，因为该蛋白高度保守，对病毒复制和增殖至关重要。此外，已经通过各种抗病毒策略来抑制病毒复制，并取得了不同程度的成功，包括靶向 Rep 的抑制肽。虽然很多努力都集中在 Rep 蛋白和抑制肽的序列表征上，但详细的结构分析一直缺失。这项研究通过计算研究了这些抑制肽中常见结构特征的存在，以及这些特征是否可以告知特定肽是否会结合 Rep 和/或干扰病毒复制。抑制肽库的分子动力学模拟表明，无论 Rep 的结合如何，仅仅拥有稳定的结构特征都不会干扰病毒复制。此外，几乎所有已知的 Rep 抑制肽都采样了一个保守的 β-折叠结构基序，可能会告知结构–结合 Rep 中的功能关系。特别是，以这种结构基序为特征的两种肽（A22 和 A64）在计算上与多种双生病毒 Rep 蛋白对接，以确定作用机制。计算对接显示这些肽利用共同的 Rep 蛋白序列基序进行结合，HHN-x 几乎所有已知的 Rep 抑制肽都对一个保守的 β-折叠结构基序进行采样，这可能会告知结合 Rep 的结构 - 功能关系。特别是，以这种结构基序为特征的两种肽（A22 和 A64）在计算上与多种双生病毒 Rep 对接蛋白质来确定作用机制。计算对接显示这些肽利用共同的 Rep 蛋白序列基序进行结合，HHN-x 几乎所有已知的 Rep 抑制肽都对一个保守的 β-折叠结构基序进行采样，这可能会告知结合 Rep 的结构 - 功能关系。特别是，以这种结构基序为特征的两种肽（A22 和 A64）在计算上与多种双生病毒 Rep 对接蛋白质来确定作用机制。计算对接显示这些肽利用共同的 Rep 蛋白序列基序进行结合，HHN-x_1/2 -Q。结果确定了 Rep 和抑制肽中在相互作用中起重要作用的残基，为构建具有广泛反应性和双生病毒物种特异性抑制剂的合理的基于结构的设计方法奠定了基础。

更新日期：2021-09-21

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