Structural basis for the inhibition mechanism of the DNA polymerase holoenzyme from mpox virus.
Structure
; 32(6): 654-661.e3, 2024 Jun 06.
Article
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| MEDLINE
| ID: mdl-38579705
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.
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Banco de datos:
MEDLINE
Asunto principal:
Proteínas Virales
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Monkeypox virus
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Microscopía por Crioelectrón
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ADN Polimerasa Dirigida por ADN
Idioma:
En
Año:
2024
Tipo del documento:
Article