Moving towards High-Resolution Descriptions of the Molecular Interactions and Structural Rearrangements of the Human Hepatitis B Core Protein
Moving towards High-Resolution Descriptions of the Molecular Interactions and Structural Rearrangements of the Human Hepatitis B Core Protein
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DOI：
10.1016/j.jmb.2008.10.020
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发表时间：
2008-12-31
影响因子：
5.6
通讯作者：
Ferguson, Neil
中科院分区：
文献类型：
--
作者：
Freund, Stefan M. V.;Johnson, Christopher M.;Ferguson, Neil
人B型肝炎病毒核心蛋白（HBc）形成二十面体衣壳并在病毒复制中起核心作用。HBc在衣壳形成（潜在的药物靶点）之前产生的关键相互作用已被证明难以进行结构表征，因为HBc积极形成衣壳。因此，我们目前对HBc相互作用的结构理解是以衣壳为中心的;这种观点受到冷冻电子显微镜分辨率和获得高质量病毒衣壳晶体的固有困难的限制。为了增强这些方法，我们使用了captase解离条件，溶液NMR和生物物理方法，以原子分辨率直接表征二聚HBc的结构特性，以及其动力学和分子间相互作用。二聚体HBc概括了HBc在衣壳背景下的结构特性和结合相互作用。抗病毒肽诱导二聚体HBc的长程结构不对称性，提供了新的见解如何配体结合可以影响HBc的不同区域之间的通信，因此，衣壳内部和衣壳外部之间。我们的工作还为详细描述涉及可溶性HBc的先前不可见的复制早期阶段铺平了道路。(C)2008爱思唯尔有限公司保留所有权利。
The human hepatitis B virus core protein (HBc) forms icosahedral capsids and plays central roles in viral replication. The critical interactions that HBc makes prior to capsid formation (potential drug targets) have proved refractory to structural characterisation as HBc aggressively forms capsids. Our current structural understanding of HBc interactions is therefore capsid-centric; and this view has been limited by the resolution of cryo-electron microscopy and the inherent difficulties in getting high-quality crystals of viral capsids. To augment these approaches, we used capsid-dissociating conditions, solution NMR, and biophysical methodologies to directly characterise, at atomic resolution, the structural properties of dimeric HBc, as well as its dynamics and intermolecular interactions. Dimeric HBc recapitulates the structural properties and binding interactions of HBc within the context of capsids. Antiviral peptides induced long-range structural asymmetry in dimeric HBc, providing new insights into how ligand binding can effect communication between different regions of HBc and, therefore, between the capsid interior and the capsid exterior. Our work also paves the way for detailed descriptions of the previously invisible early stages of replication involving soluble HBc. (C) 2008 Elsevier Ltd. All rights reserved.