Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
Department of Internal Medicine, Mayo Clinic, Rochester, MN 55902, USA.
Viruses. 2022 Feb 17;14(2):414. doi: 10.3390/v14020414.
Various adenoviruses are being used as viral vectors for the generation of vaccines against chronic and emerging diseases (e.g., AIDS, COVID-19). Here, we report the improved capsid structure for one of these vectors, human adenovirus D26 (HAdV-D26), at 3.4 Å resolution, by reprocessing the previous cryo-electron microscopy dataset and obtaining a refined model. In addition to overall improvements in the model, the highlights of the structure include (1) locating a segment of the processed peptide of VIII that was previously believed to be released from the mature virions, (2) reorientation of the helical appendage domain (APD) of IIIa situated underneath the vertex region relative to its counterpart observed in the cleavage defective () mutant of HAdV-C5 that resulted in the loss of interactions between the APD and hexon bases, and (3) the revised conformation of the cleaved N-terminal segments of pre-protein VI (pVIn), located in the hexon cavities, is highly conserved, with notable stacking interactions between the conserved His13 and Phe18 residues. Taken together, the improved model of HAdV-D26 capsid provides a better understanding of protein-protein interactions in HAdV capsids and facilitates the efforts to modify and/or design adenoviral vectors with altered properties. Last but not least, we provide some insights into clotting factors (e.g., FX and PF4) binding to AdV vectors.
各种腺病毒被用作生成针对慢性和新兴疾病（例如艾滋病、COVID-19）疫苗的病毒载体。在这里，我们通过重新处理以前的冷冻电镜数据集并获得改进的模型，报告了其中一种载体人腺病毒 D26（HAdV-D26）的改进衣壳结构，分辨率为 3.4Å。除了模型的整体改进外，结构的亮点包括：（1）定位了以前认为从成熟病毒体中释放的 VIII 加工肽的一段；（2）IIIa 的螺旋附加结构域（APD）相对于其在 HAdV-C5 的无切割缺陷（）突变体中观察到的位置重新定向，导致 APD 与六邻体碱基之间的相互作用丧失；（3）位于六邻体腔中的前蛋白 VI（pVIn）的切割 N 端片段的修订构象高度保守，保守的 His13 和 Phe18 残基之间存在显著的堆积相互作用。总之，改进的 HAdV-D26 衣壳模型更好地理解了 HAdV 衣壳中的蛋白质-蛋白质相互作用，并促进了修饰和/或设计具有改变性质的腺病毒载体的努力。最后但同样重要的是，我们提供了一些关于凝血因子（例如 FX 和 PF4）与 AdV 载体结合的见解。
