Crystal Structure of the Vaccinia Virus DNA Polymerase Holoenzyme Subunit D4 in Complex with the A20 N-Terminal Domain

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Vaccinia virus is the prototype of the orthopoxvirus genus which includes other pathogens infecting humans and variola virus which was eradicated in the late 70's. Vaccinia virus DNA synthesis relies on three proteins: these are E9, the DNA polymerase bound to its heterodimeric cofactor D4/A20. To date, the molecular mechanism involved in poxvirus DNA replication remains poorly understood. Here, we present the high-resolution crystal structure of a complex formed by D4 and the first 50 residues of A20 (A201–50) that are necessary and sufficient for binding. The structure of D4/A201–50 reveals the contact surface engaged in the D4/A20 interaction in great detail. Interestingly, we could show that known small molecule inhibitors of vaccinia virus DNA synthesis selected for their ability to interfere with the D4/A20 interface could be docked onto the D4 surface where they mimic several aspects of the interacting A20 molecule. Finally, we present a model of D4/A20 in complex with DNA that allows us to discuss the role of mutations affecting the D4/A20 cofactor. Altogether, our structure gives new insights into the assembly of the vaccinia virus DNA polymerase cofactor and will be useful for the design of new antiviral compounds targeting the D4/A20 interaction.

Vyšlo v časopise: Crystal Structure of the Vaccinia Virus DNA Polymerase Holoenzyme Subunit D4 in Complex with the A20 N-Terminal Domain. PLoS Pathog 10(3): e32767. doi:10.1371/journal.ppat.1003978
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1003978

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