Potential drug targets identified in study of African swine fever virus enzymes

African swine fever virus is the only mammalian infectious virus that encodes DNA topoisomerase type II and has caused severe damage to the global swine industry in recent years. Safe and effective commercial vaccines and drugs are still lacking.

Therefore, research on virus-encoded type II DNA topoisomerase pP1192R is helpful in providing an important theoretical basis for drug development against African swine fever.

According to a study published in Natural communications On May 30, researchers led by Professor Rao Zihe from the Institute of Biophysics of the Chinese Academy of Sciences used various experimental techniques, including single-particle electron cryomicroscopy, X-ray crystallography and biochemical experiments, to untangle conformational dynamics. of DNA topoisomerase pP1192R type II encoded by the complete African swine fever virus in complex with nucleic acids and verify its enzymatic activity in vitro.

In this study, high-resolution structures of three different conformations of the pP1192R protein in the apo state were obtained, showing different opening directions of the central structural domain of the protein.

Researchers overcame the challenge of instability of the ATPase N-terminal domain by adding specific nucleic acid molecules and, after sample optimization, capturing the structure of the complete DNA-bound protein complex linear.

The structure exhibited significant bending of the double-stranded DNA, causing a local transition from the “form B” to the “form A” configuration.

They directly observed the image of protein-binding plasmid-DNA crossing using atomic force microscopy and confirmed this binding feature. Using molecular docking, researchers connected two different types of DNA topoisomerase type II inhibitors as potential starting points for drug design.

This study comprehensively elucidates the structure and function of virus-encoded type II DNA topoisomerase through various experimental techniques, reveals the molecular mechanism of virus type II DNA topoisomerase, provides potential strategies for engineering of inhibitors, establishes a theoretical basis for the prevention and control of the African swine fever epidemic, and proposes potential intervention strategies to mitigate the impact of the African swine fever virus.