结构和突变发生揭示了KSHV复制必需的状蛋白相互作用
Xinghong Dai1,2,3, Danyang Gong3, Hanyoung Lim1
1Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles (UCLA), Los Angeles, California 90095, USA.
Nature
|January 18, 2018
概括
我们确定了卡波西肉瘤相关疹病毒 (KSHV) 囊的原子结构, 这一发现为开发KSHV抗病毒疗法提供了新的目标.
科学领域:
- 结构生物学
- 病毒学
- 生物化学
背景情况:
- 卡波西肉瘤相关的疹病毒 (KSHV) 导致卡波西肉瘤,这是艾滋病患者和撒哈拉以南非洲普遍存在的癌症.
- 疹病毒囊体在DNA基因组的高压下是大型复杂的结构, 使它们成为抗病毒开发的具有挑战性的目标.
- 了解囊组合和基因组包装对于向疹病毒复制至关重要.
研究的目的:
- 确定KSHV体的高分辨率原子结构.
- 绘制体稳定性和组装中的分子相互作用.
- 确定抗病毒药物开发的潜在目标.
主要方法:
- 用电子计数实现4.2 Å分辨率的冷电子显微镜 (冷EM).
- 构建KSHV体的原子模型,包括主要体蛋白 (MCP),最小体蛋白 (SCP) 和三重蛋白 (Tri1,Tri2).
- 突变性研究,以验证已识别的蛋白相互作用部位的功能作用.
主要成果:
- 生成了KSHV体的详细原子模型,揭示了46个独特的蛋白质对应物.
- 确定了MCP上的一个关键槽,与SCP进行介导相互作用以稳定状结构.
- MCP子单元之间的多重相互作用接口,包括堆叠的发针,二硫化键和N-lasso/二聚化域,有助于体的强度.
- 通过Tri1 N相互作用,三重蛋白 (Tri1/Tri2) 已被证明可以固底,堵塞孔,并加强结构.
- 突变性证实了MCP N-lasso和Tri1 N-域的重要作用.
结论:
- 高分辨率的KSHV囊结构阐明了囊完整性所必需的复杂的蛋白质-蛋白质相互作用.
- 已识别的相互作用热点,特别是涉及MCP和SCP,为结构导向抗病毒药物设计提供了基础.
- 模仿SCP的多体在抑制KSHV溶性复制方面表现出潜力,验证了治疗策略.
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