EMD-36069

Single-particle
2.79 Å
EMD-36069 Deposition: 01/05/2023
Map released: 08/05/2024
Last modified: 05/06/2024
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links

EMD-36069

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

EMD-36069

Single-particle
2.79 Å
EMD-36069 Deposition: 01/05/2023
Map released: 08/05/2024
Last modified: 05/06/2024
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links
Sample Organism: Monkeypox virus, DNA molecule
Sample: Monkeypox virus replication holoenzyme F8-A22-E4 in complex with DNA duplex and cidofovir diphosphate
Fitted models: 8j8g (Avg. Q-score: 0.471)

Deposition Authors: Xu Y, Wu Y, Wu X, Zhang Y, Yang Y, Li D, Yang B, Gao K, Zhang Z, Dong C, Tang X, Dong H
Structural basis of human mpox viral DNA replication inhibition by brincidofovir and cidofovir.
Xu Y, Wu Y, Wu X, Zhang Y, Yang Y, Li D, Yang B, Gao K, Zhang Z, Dong C
(2024) Int J Biol Macromol , 270 , 132231 - 132231
PUBMED: 38735603
DOI: doi:10.1016/j.ijbiomac.2024.132231
ISSN: 0141-8130
ASTM: IJBMDR
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.