乙型肝炎病毒核心蛋白变构调节剂可以扭曲和破坏完整的衣

StephenW

Elife. 2018 Jan 29;7. pii: e31473. doi: 10.7554/eLife.31473.
Hepatitis B virus core protein allosteric modulators can distort and disrupt intact capsids.Schlicksup CJ1, Wang JC1,2, Francis S3, Venkatakrishnan B1, Turner WW3, VanNieuwenhze M4, Zlotnick A1.
Author information
1Department of Molecular and Cellular Biochemistry, Indiana University, Bloomington, United States.2Indiana University Electron Microscopy Center, Bloomington, United States.3Assembly Biosciences, Carmel, United States.4Department of Chemistry, Indiana University, Bloomington, United States.

AbstractDefining mechanisms of direct-acting antivirals facilitates drug development and our understanding of virus function. Heteroaryldihydropyrimidines (HAPs) inappropriately activate assembly of hepatitis B virus (HBV) core protein (Cp), suppressing formation of virions. We examined a fluorophore-labeled HAP, HAP-TAMRA. HAP-TAMRA induced Cp assembly and also bound pre-assembled capsids. Kinetic and spectroscopic studies imply that HAP-binding sites are usually not available but are bound cooperatively. Using cryo-EM, we observed that HAP-TAMRA asymmetrically deformed capsids, creating a heterogeneous array of sharp angles, flat regions, and outright breaks. To achieve high resolution reconstruction (<4 Å), we introduced a disulfide crosslink that rescued particle symmetry. We deduced that HAP-TAMRA caused quasi-sixfold vertices to become flatter and fivefold more angular. This transition led to asymmetric faceting. That a disordered crosslink could rescue symmetry implies that capsids have tensegrity properties. Capsid distortion and disruption is a new mechanism by which molecules like the HAPs can block HBV infection.


KEYWORDS: biochemistry; cryo-EM; direct acting antiviral; hepatitis B virus; image reconstruction; infectious disease; microbiology; self-assembly; virus

PMID:29377794DOI:10.7554/eLife.31473

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StephenW

网上生活。 2018年1月29日; 7。 pii：e31473。 doi：10.7554 / eLife.31473。
乙型肝炎病毒核心蛋白变构调节剂可以扭曲和破坏完整的衣壳。
Schlicksup CJ1，Wang JC1,2，Francis S3，Venkatakrishnan B1，Turner WW3，VanNieuwenhze M4，Zlotnick A1。
作者信息

1
    印度尼西亚大学分子与细胞生物化学系，美国布卢明顿。
2
    印第安纳大学电子显微镜中心，布卢明顿，美国。
3
    装配生物科学，卡梅尔，美国。
4
    印第安那大学化学系，布卢明顿，美国。

抽象

定义直接作用抗病毒药物的机制有利于药物开发和我们对病毒功能的理解。杂芳基二氢嘧啶（HAPs）不适当地激活乙型肝炎病毒（HBV）核心蛋白（Cp）的组装，抑制病毒体的形成。我们检查了荧光标记的HAP HAP-TAMRA。 HAP-TAMRA诱导Cp组装并且还结合预装配的衣壳。动力学和光谱学研究意味着HAP结合位点通常不可用，但是被合作地结合。使用cryo-EM，我们观察到HAP-TAMRA不对称变形的衣壳，形成了尖锐的角度，平坦的区域和完全的断裂的异构阵列。为了实现高分辨率重建（<4？），我们引入了一个二硫键交联，拯救了粒子的对称性。我们推断HAP-TAMRA导致准六重顶点变得平坦和五倍角度。这种转变导致了不对称的刻面。无序交联可以挽救对称意味着衣壳具有张拉整体性质。衣壳变形和破坏是HAPs等分子阻断HBV感染的新机制。
关键词：

生物化学;冷冻电镜;直接作用的抗病毒药;乙肝病毒;影像重建;传染病;微生物学;自组装;病毒

结论：
    29377794
DOI：
    10.7554 / eLife.31473