Cryo-EM structure of the EBV ribonucleotide reductase BORF2 and mechanism of APOBEC3B inhibition

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-angstrom(2) 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.

Automated summary

Viruses have evolved various mechanisms to evade immune responses. A recent study found that the Epstein-Barr virus (EBV) can neutralize the nuclear DNA cytosine deaminase APOBEC3B through its ribonucleotide reductase subunit BORF2. Cryo-EM studies of APOBEC3B-BORF2 complexes revealed a large binding surface that effectively blocks APOBEC3B's active site. This understanding of the pathogen-host interaction has the potential to inform the development of drugs that can disrupt this interaction and enhance the antiviral activity of APOBEC3B. Additionally, it may also have implications for the development of inhibitors targeting DNA deaminases, which are involved in cancer mutagenesis.