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-Structure paper
タイトル | Structural basis for the inhibition mechanism of the DNA polymerase holoenzyme from mpox virus. |
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ジャーナル・号・ページ | Structure, Vol. 32, Issue 6, Page 654-661.e3, Year 2024 |
掲載日 | 2024年6月6日 |
著者 | Yaping Shen / Yaning Li / Renhong Yan / |
PubMed 要旨 | 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 ...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. |
リンク | Structure / PubMed:38579705 |
手法 | EM (単粒子) |
解像度 | 3.0 - 3.06 Å |
構造データ | EMDB-36960, PDB-8k8s: EMDB-36962, PDB-8k8u: EMDB-36963: the local map of DNA and Ara-CTP binding site EMDB-36964: the local map of DNA and dCTP binding site |
化合物 | ChemComp-MG: ChemComp-HF4: ChemComp-HOH: ChemComp-CTP: |
由来 |
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キーワード | VIRAL PROTEIN/DNA / RECOMBINATION / REPLICATION / VIRAL PROTEIN-DNA COMPLEX |