Type-specific epitope locations revealed by X-ray crystallographic study of adenovirus type 5 hexon
Type-specific epitope locations revealed by X-ray crystallographic study of adenovirus type 5 hexon
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DOI：
10.1006/mthe.1999.0001
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发表时间：
2000-01-01
影响因子：
12.4
通讯作者：
Burnett, RM
中科院分区：
文献类型：
--
作者：
Rux, JJ;Burnett, RM
使用腺病毒作为基因治疗载体的主要障碍是宿主对六邻体的免疫应答，六邻体是二十面体衣壳的主要蛋白质组分。一种解决方案在于用修饰的或嵌合的苍鹭创建新的载体，以逃避对天然六邻体的免疫应答。来自人类5型腺病毒（ad 5）的heron的晶体结构，主要用于基因治疗，已经被确定以促进这种分子的设计。由于951个氨基酸（aa）ad 5六邻体序列与ad 2（967 aa; 86% aa同一性）密切相关，因此通过用从已知ad 2六邻体构建的模型进行分子置换来解析ad 5结构。在优化过程中，超过25%的序列被重新分配，导致两个表位区域从ad 2模型中的隐藏位置重新定位到ad 5分子顶部的外部位点。所得模型与晶体学数据更一致，同时保持ad 2六邻体的整体拓扑结构。这项工作表明，所有的苍鹭有相同的基本折叠和ad 5六邻体结构提供了一个准确的和有代表性的模型设计新的腺病毒载体。
A major obstacle to the use of adenovirus as a vector for gene therapy is the host immune response to hexon, the major protein component of the icosahedral capsid. A solution lies in creating novel vectors with modified or chimeric herons to evade the immune response to native hexon. The crystal structure of heron from human adenovirus type 5 (ad5), the type primarily used for gene therapy, has been determined to facilitate the design of such molecules. As the 951-amino-acid (aa) ad5 hexon sequence is closely related to that of ad2 (967 aa; 86% aa identity), the ad5 structure was solved by molecular replacement with a model constructed from the known ad2 hexon. During refinement, greater than 25% of the sequence was reassigned, resulting in a relocation of two epitope regions, from buried positions in the ad2 model to external sites at the top of the ad5 molecule. The resultant model is in better agreement with crystallographic data, while maintaining the overall topology of ad2 hexon. This work suggests that all herons have the same basic fold and that the ad5 hexon structure provides an accurate and representative model for designing new adenovirus vectors.