8X8Q

Structure of enterovirus protease in complex host factor

Summary for 8X8Q

• Entry DOI: 10.2210/pdb8x8q/pdb
• EMDB information: 38156
• Descriptor: Actin-histidine N-methyltransferase, 2A protein (Fragment), ZINC ION (3 entities in total)
• Functional Keywords: host protein, viral protein, cell invasion, cell cycle
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 83969.87

Authors

Gao, X.,Cui, S. (deposition date: 2023-11-28, release date: 2024-05-29, Last modification date: 2025-07-02)

Primary citation

Gao, X.,Wang, B.,Zhu, K.,Wang, L.,Qin, B.,Shang, K.,Ding, W.,Wang, J.,Cui, S.
The EV71 2A protease occupies the central cleft of SETD3 and disrupts SETD3-actin interaction.
Nat Commun, 15:4176-4176, 2024

PubMed Abstract: SETD3 is an essential host factor for the replication of a variety of enteroviruses that specifically interacts with viral protease 2A. However, the interaction between SETD3 and the 2A protease has not been fully characterized. Here, we use X-ray crystallography and cryo-electron microscopy to determine the structures of SETD3 complexed with the 2A protease of EV71 to 3.5 Å and 3.1 Å resolution, respectively. We find that the 2A protease occupies the V-shaped central cleft of SETD3 through two discrete sites. The relative positions of the two proteins vary in the crystal and cryo-EM structures, showing dynamic binding. A biolayer interferometry assay shows that the EV71 2A protease outcompetes actin for SETD3 binding. We identify key 2A residues involved in SETD3 binding and demonstrate that 2A's ability to bind SETD3 correlates with EV71 production in cells. Coimmunoprecipitation experiments in EV71 infected and 2A expressing cells indicate that 2A interferes with the SETD3-actin complex, and the disruption of this complex reduces enterovirus replication. Together, these results reveal the molecular mechanism underlying the interplay between SETD3, actin, and viral 2A during virus replication.

PubMed: 38755176
DOI: 10.1038/s41467-024-48504-w

Experimental method

ELECTRON MICROSCOPY (3.14 Å)