8K8S

F8-A22-E4 complex of MPXV in complex with DNA and Ara-CTP

Summary for 8K8S

• Entry DOI: 10.2210/pdb8k8s/pdb
• EMDB information: 36960
• Descriptor: DNA polymerase F8, Uracil-DNA glycosylase E4, DNA polymerase processivity factor component A20, ... (8 entities in total)
• Functional Keywords: recombination, replication, viral protein-dna complex, viral protein/dna
• Biological source: Monkeypox virus; More
• Total number of polymer chains: 5
• Total formula weight: 200449.79

Authors

Shen, Y.P.,Li, Y.N.,Yan, R.H. (deposition date: 2023-07-31, release date: 2024-06-05, Last modification date: 2024-06-19)

Primary citation

Shen, Y.,Li, Y.,Yan, R.
Structural basis for the inhibition mechanism of the DNA polymerase holoenzyme from mpox virus.
Structure, 32:654-661.e3, 2024

PubMed Abstract: There are three key components at the core of the mpox virus (MPXV) DNA polymerase holoenzyme: DNA polymerase F8, processivity factors A22, and the Uracil-DNA glycosylase E4. The holoenzyme is recognized as a vital antiviral target because MPXV replicates in the cytoplasm of host cells. Nucleotide analogs such as cidofovir and cytarabine (Ara-C) have shown potential in curbing MPXV replication and they also display promise against other poxviruses. However, the mechanism behind their inhibitory effects remains unclear. Here, we present the cryo-EM structure of the DNA polymerase holoenzyme F8/A22/E4 bound with its competitive inhibitor Ara-C-derived cytarabine triphosphate (Ara-CTP) at an overall resolution of 3.0 Å and reveal its inhibition mechanism. Ara-CTP functions as a direct chain terminator in proximity to the deoxycytidine triphosphate (dCTP)-binding site. The extra hydrogen bond formed with Asn665 makes it more potent in binding than dCTP. Asn665 is conserved among eukaryotic B-family polymerases.

PubMed: 38579705
DOI: 10.1016/j.str.2024.03.004

Experimental method

ELECTRON MICROSCOPY (3.06 Å)