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Structure-function analysis of enterovirus protease 2A in complex with its essential host factor SETD3.

ABSTRACT: Enteroviruses cause a number of medically relevant and widespread human diseases with no approved antiviral therapies currently available. Host-directed therapies present an enticing option for this diverse genus of viruses. We have previously identified the actin histidine methyltransferase SETD3 as a critical host factor physically interacting with the viral protease 2A. Here, we report the 3.5 Å cryo-EM structure of SETD3 interacting with coxsackievirus B3 2A at two distinct interfaces, including the substrate-binding surface within the SET domain. Structure-function analysis revealed that mutations of key residues in the SET domain resulted in severely reduced binding to 2A and complete protection from enteroviral infection. Our findings provide insight into the molecular basis of the SETD3-2A interaction and a framework for the rational design of host-directed therapeutics against enteroviruses.

SUBMITTER: Peters CE

PROVIDER: S-EPMC9453702 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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Structure-function analysis of enterovirus protease 2A in complex with its essential host factor SETD3.

Peters Christine E CE Schulze-Gahmen Ursula U Eckhardt Manon M Jang Gwendolyn M GM Xu Jiewei J Pulido Ernst H EH Bardine Conner C Craik Charles S CS Ott Melanie M Gozani Or O Verba Kliment A KA Hüttenhain Ruth R Carette Jan E JE Krogan Nevan J NJ

Nature communications 20220908 1

Enteroviruses cause a number of medically relevant and widespread human diseases with no approved antiviral therapies currently available. Host-directed therapies present an enticing option for this diverse genus of viruses. We have previously identified the actin histidine methyltransferase SETD3 as a critical host factor physically interacting with the viral protease 2A. Here, we report the 3.5 Å cryo-EM structure of SETD3 interacting with coxsackievirus B3 2A at two distinct interfaces, inclu ...[more]

PMID: 36075902

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Project description:Enterovirus 71 (EV71) is a major pathogen that causes hand, foot, and mouth disease (HFMD) in infants and children. Notably, no clinically approved drugs specifically target EV71. The EV71 2A protease (2Apro), a cysteine protease produced by the virus, is essential for the virus' replication and has a significant impact on the functioning of host cells. Thus, it presents a valuable target for the discovery of antiviral medications. In this study, based on the monomers and their derivatives in the Library of Traditional Chinese Medicine (TCM), we performed virtual screening and biological experiments. We identified a derivative of a traditional herbal monomer, Etoposide, commonly isolated from the roots and rhizomes of Podophyllum spp. Etoposide inhibited replication of EV71 A, B, C, and CVA16 viruses in a concentration-dependent manner in a variety of cell lines with minimal cytotoxicity. Furthermore, both molecular dynamics simulations and site-directed mutagenesis assays revealed that Etoposide inhibited the activity of the EV71 2A protease by mainly binding to two residues, Y89 and P107. The findings indicate that Etoposide serves as a promising inhibitor of the EV71 2Apro, demonstrating strong antiviral properties and positioning itself as a formidable candidate for clinical trials against EV71.IMPORTANCEWe first used a drug screening approach focused on monomeric compounds and their derivatives from traditional Chinese medicine to identify an EV71 2Apro inhibitor-Etoposide. We then performed biological experiments to validate that Etoposide suppresses the replication of the EV71 virus in a concentration-dependent manner with minimal cytotoxicity to various cell lines. Remarkably, it shows inhibitory activity against EV71 A, B, C, and CVA16, suggesting that Etoposide may be a potential broad-spectrum inhibitor. We revealed a novel mechanism that Etoposide inhibits EV71 proliferation by targeting 2Apro, and the interactions with Y89 and P107 are of great importance. The findings suggest that Etoposide serves as a promising inhibitor of EV71 2Apro, demonstrating significant antiviral properties. It stands out as a strong candidate for broad-spectrum applications in clinical research.

Dataset Information

Structure-function analysis of enterovirus protease 2A in complex with its essential host factor SETD3.

Publications

Structure-function analysis of enterovirus protease 2A in complex with its essential host factor SETD3.

Similar Datasets

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