Shaban Nadine M, Yan Rui, Shi Ke, Moraes Sofia N, Cheng Adam Z, Carpenter Michael A, McLellan Jason S, Yu Zhiheng, Harris Reuben S
Department of Biochemistry, Molecular Biology, and Biophysics, Institute for Molecular Virology, Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA.
Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA 55416, USA.
Sci Adv. 2022 Apr 29;8(17):eabm2827. doi: 10.1126/sciadv.abm2827. Epub 2022 Apr 27.
Viruses use a plethora of mechanisms to evade immune responses. A recent example is neutralization of the nuclear DNA cytosine deaminase APOBEC3B by the Epstein-Barr virus (EBV) ribonucleotide reductase subunit BORF2. Cryo-EM studies of APOBEC3B-BORF2 complexes reveal a large >1000-Å binding surface composed of multiple structural elements from each protein, which effectively blocks the APOBEC3B active site from accessing single-stranded DNA substrates. Evolutionary optimization is suggested by unique insertions in BORF2 absent from other ribonucleotide reductases and preferential binding to APOBEC3B relative to the highly related APOBEC3A and APOBEC3G enzymes. A molecular understanding of this pathogen-host interaction has potential to inform the development of drugs that block the interaction and liberate the natural antiviral activity of APOBEC3B. In addition, given a role for APOBEC3B in cancer mutagenesis, it may also be possible for information from the interaction to be used to develop DNA deaminase inhibitors.
病毒利用多种机制来逃避免疫反应。最近的一个例子是，爱泼斯坦-巴尔病毒（EBV）的核糖核苷酸还原酶亚基BORF2对核DNA胞嘧啶脱氨酶APOBEC3B的中和作用。对APOBEC3B-BORF2复合物的冷冻电镜研究揭示了一个由每种蛋白质的多个结构元件组成的大于1000埃的大结合表面，这有效地阻止了APOBEC3B活性位点接近单链DNA底物。BORF2中存在其他核糖核苷酸还原酶所没有的独特插入序列，并且相对于高度相关的APOBEC3A和APOBEC3G酶，它优先与APOBEC3B结合，这表明了其进化优化。对这种病原体与宿主相互作用的分子理解有可能为开发阻断这种相互作用并释放APOBEC3B天然抗病毒活性的药物提供信息。此外，鉴于APOBEC3B在癌症诱变中的作用，从这种相互作用中获得的信息也有可能用于开发DNA脱氨酶抑制剂。
