In July 2022, the World Health Organization (WHO) announced that monkeypox was a public health emergency of international concern. And, as of early December 2022, more than 82,000 human monkeypox cases have been confirmed in 110 countries worldwide. New preventative and therapeutic measures against the virus are needed.

Monkeypox is caused by monkeypox virus, an enveloped double-stranded DNA virus that belongs to the Orthopoxvirus genus of the Poxviridae family. The monkeypox virus has its own DNA polymerase F8 which, when together with the processive cofactors A22 and E4, constitutes the polymerase holoenzyme for genome replication.

Now, researchers present a high-resolution structure of the monkeypox virus DNA polymerase holoenzyme—a complex that plays a key role in the genome replication process of the virus. The findings reveal the mechanism that underlies monkeypox virus genome replication and could be used to guide the development of antiviral drugs.

This work is published in Science, in the article, “Structure of monkeypox virus DNA polymerase holoenzyme.”

Qi Peng, PhD, and colleagues at the CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology at the Chinese Academy of Sciences in Beijing, used cryo-electron microscopy to determine a high-resolution structure of the monkeypox virus DNA polymerase holoenzyme.

They determined the holoenzyme structure in complex with DNA using cryo-electron microscopy at the global resolution of ~2.8 Å. According to the findings, the holoenzyme possesses an architecture that indicates a “forward sliding clamp” mechanism for DNA replication. Monkeypox virus polymerase has a similar DNA binding mode to other B-family DNA polymerases from different species. These findings reveal the mechanism of the monkeypox virus genome replication and may guide the development of anti-poxvirus drugs.