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CryoEM structure of the EBV ribonucleotide reductase BORF2 and mechanism of APOBEC3B inhibition

Shaban, N.; Yan, R.; Shi, K.; Moraes, S.; Cheng, A.; Carpenter, M.; McLellan, J. S.; Zhiheng, Y.; Harris, R.

2021-08-31 microbiology
10.1101/2021.08.30.458246 bioRxiv
Show abstract

Viruses use a plethora of mechanisms to evade immune responses. A new 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 [A]2 binding surface comprised 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. An atomic understanding of this novel pathogen-host interaction may contribute to the development of drugs that block the interaction and liberate the natural antiviral activity of APOBEC3B. One-Sentence SummaryThese studies show how a conserved viral nucleotide metabolism protein is repurposed to inhibit a potent antiviral factor.

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