Cryo-EM structures of human monkeypox viral replication complexes with and without DNA duplex

Yunxia Xu, Yaqi Wu, Yuanyuan Zhang, Ruixin Fan, Yaxue Yang, Danyang Li, Shimin Zhu, Biao Yang, Zhengyu Zhang & Changjiang Dong

Cell Research (2023)

https://www.nature.com/articles/s41422-023-00796-1

Abstract

MPXV, belonging to the orthopoxvirus genus of the poxviridae family, is a large enveloped DNA virus with a double-stranded DNA (dsDNA) molecule of ~197 kilobase pairs (kb), which encodes ~181 proteins.3 The life cycle of MPXV takes place entirely in the cytoplasm of infected cells, where MPXV replicates its DNA by a DNA replication machinery that consists of the catalytic subunit F8, a B-family DNA polymerase, and a processivity factor heterodimer A22 and E4 (Fig. 1a).3,4 E4, a uracil-DNA glycosylase that removes uracil from DNA, is linked to F8 by A22. Unlike RNA viruses, the dsDNA poxviruses have much lower mutation frequency as their DNA replication machineries enable coupling of DNA replication, proofreading and base excision repair.5 In addition, the DNA replication machinery is an important drug target.6 Here we report cryogenic electron microscopy (cryo-EM) structures of MPXV DNA replication machinery F8–A22–E4 in the presence and absence of DNA, providing insights into MPXV DNA replication and development of drugs against MPXV.