8WWO

Crystal structure of the AFSV topoisomerase ATPase domain in complex with AMPPNP

Summary for 8WWO

• Entry DOI: 10.2210/pdb8wwo/pdb
• Descriptor: DNA topoisomerase 2, PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER, MAGNESIUM ION, ... (4 entities in total)
• Functional Keywords: topoisomerase, viral protein
• Biological source: African swine fever virus
• Total number of polymer chains: 4
• Total formula weight: 186815.21

Authors

Kuang, W.,Deng, Z. (deposition date: 2023-10-26, release date: 2024-02-21, Last modification date: 2024-07-10)

Primary citation

Kuang, W.,Zhao, Y.,Li, J.,Deng, Z.
Structure-function analysis of the ATPase domain of African swine fever virus topoisomerase.
Mbio, 15:e0308623-e0308623, 2024

PubMed Abstract: Type II topoisomerase utilizes the energy from ATP hydrolysis to alter DNA topology during genome replication and transcription. The ATPase domain of this enzyme is required for ATP hydrolysis and plays a crucial role in coupling DNA binding and ATP turnover with the DNA strand passage reaction. The African swine fever virus (ASFV) specifically encodes a topoisomerase II (topo II), which is critical for viral replication and an attractive target for antiviral development. Here, we present a high-resolution crystal structure of the ASFV topo II ATPase domain complexed with the substrate analog AMPPNP. Structural comparison reveals that the ASFV topo II ATPase domain shares a conserved overall structure with its homologs from eukaryotes and prokaryotes but also has three characteristic regions, including the intra-molecular interface formed by the ATP-lid and QTK loop as well as helix α9, the K-loop in the transducer domain, and the antennae-like α-helix at the ATP binding domain. Mutating the key residues within these three regions impairs or abolishes the basal and DNA-stimulated ATPase activities and reduces or eliminates the relaxation activity of the holoenzyme. Our data indicate that all three regions are functionally important for the ATPase and relaxation activities and strongly suggest that ATP hydrolysis, DNA binding, and strand passage are highly coupled and managed by the allosteric coordination of multiple domains of the type II topoisomerase. Moreover, we find a promising druggable pocket in the dimeric interface of the ASFV topo II ATPase domain, which will benefit future anti-ASFV drug development.

PubMed: 38411066
DOI: 10.1128/mbio.03086-23

Experimental method

X-RAY DIFFRACTION (2.2 Å)