The structure of monkeypox virus 2'-O-ribose methyltransferase VP39 in complex with sinefungin provides the foundation for inhibitor design

Monkeypox is an emerging, rapidly spreading disease with pandemic potential. It is caused by the monkeypox virus (MPXV), a dsDNA virus from the Poxviridae family, that replicates in the cytoplasm and must encode for its own RNA processing machinery including the capping machinery. Here, we present the crystal structure of its 2-O-RNA methyltransferase (MTase) VP39 in complex with the pan-MTase inhibitor sinefungin. A comparison of this 2-O RNA MTase with enzymes from unrelated ssRNA viruses (SARS-CoV-2 and Zika) reveals a surprisingly conserved sinefungin binding mode implicating that a single inhibitor could be used against unrelated viral families.