8J8F

Monkeypox virus DNA replication holoenzyme F8, A22 and E4 in complex with a DNA duplex and dCTP

8J8F の概要

• エントリーDOI: 10.2210/pdb8j8f/pdb
• 関連するPDBエントリー: 8HDZ 8HOY 8HPA 8J86
• EMDBエントリー: 36068
• 分子名称: DNA polymerase, E4R, DNA polymerase processivity factor component A20, ... (7 entities in total)
• 機能のキーワード: monkeypox virus, dna replication holoenzyme, dna replication machinery, dna polymerase, b-family dna polymerase, uracil-dna glycosylase, mpxv, orthopoxvirus, poxviridae, dna processivity factor, viral protein
• 由来する生物種: Monkeypox virus; 詳細
• タンパク質・核酸の鎖数: 5
• 化学式量合計: 216760.49

構造登録者

Xu, Y.,Wu, Y.,Wu, X.,Zhang, Y.,Yang, Y.,Li, D.,Yang, B.,Gao, K.,Zhang, Z.,Dong, C. (登録日: 2023-05-01, 公開日: 2024-05-08, 最終更新日: 2024-06-05)

主引用文献

Xu, Y.,Wu, Y.,Wu, X.,Zhang, Y.,Yang, Y.,Li, D.,Yang, B.,Gao, K.,Zhang, Z.,Dong, C.
Structural basis of human mpox viral DNA replication inhibition by brincidofovir and cidofovir.
Int.J.Biol.Macromol., 270:132231-132231, 2024

PubMed Abstract: Mpox virus has wildly spread over 108 non-endemic regions in the world since May 2022. DNA replication of mpox is performed by DNA polymerase machinery F8-A22-E4, which is known as a great drug target. Brincidofovir and cidofovir are reported to have broad-spectrum antiviral activity against poxviruses, including mpox virus in animal models. However, the molecular mechanism is not understood. Here we report cryogenic electron microscopy structures of mpox viral F8-A22-E4 in complex with a DNA duplex, or dCTP and the DNA duplex, or cidofovir diphosphate and the DNA duplex at resolution of 3.22, 2.98 and 2.79 Å, respectively. Our structural work and DNA replication inhibition assays reveal that cidofovir diphosphate is located at the dCTP binding position with a different conformation to compete with dCTP to incorporate into the DNA and inhibit DNA synthesis. Conformation of both F8-A22-E4 and DNA is changed from the pre-dNTP binding state to DNA synthesizing state after dCTP or cidofovir diphosphate is bound, suggesting a coupling mechanism. This work provides the structural basis of DNA synthesis inhibition by brincidofovir and cidofovir, providing a rational strategy for new therapeutical development for mpox virus and other pox viruses.

PubMed: 38735603
DOI: 10.1016/j.ijbiomac.2024.132231

実験手法

ELECTRON MICROSCOPY (2.98 Å)