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.

Actin histidine methyltransferase SETD3 is a host factor critical for the replication of enteroviruses. Here, the authors report the 3.5 Å cryoEM structure of SETD3 interacting with enterovirus CV-B3 2A protease, defining the actin-binding SET domain as essential for virus replication.

Details

Title
Structure-function analysis of enterovirus protease 2A in complex with its essential host factor SETD3
Author
Peters, Christine E. 1 ; Schulze-Gahmen, Ursula 2   VIAFID ORCID Logo  ; Eckhardt, Manon 3   VIAFID ORCID Logo  ; Jang, Gwendolyn M. 3   VIAFID ORCID Logo  ; Xu, Jiewei 3 ; Pulido, Ernst H. 3   VIAFID ORCID Logo  ; Bardine, Conner 4 ; Craik, Charles S. 4   VIAFID ORCID Logo  ; Ott, Melanie 5   VIAFID ORCID Logo  ; Gozani, Or 6   VIAFID ORCID Logo  ; Verba, Kliment A. 7   VIAFID ORCID Logo  ; Hüttenhain, Ruth 3   VIAFID ORCID Logo  ; Carette, Jan E. 1   VIAFID ORCID Logo  ; Krogan, Nevan J. 8   VIAFID ORCID Logo 

1  Stanford University School of Medicine, Department of Microbiology and Immunology, Stanford, USA (GRID:grid.168010.e) (ISNI:0000000419368956) 
2  The J. David Gladstone Institutes, Gladstone Institute of Virology, San Francisco, USA (GRID:grid.249878.8) (ISNI:0000 0004 0572 7110); QBI Coronavirus Research Group (QCRG), San Francisco, USA (GRID:grid.249878.8); University of California San Francisco, Quantitative Biosciences Institute, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811) 
3  QBI Coronavirus Research Group (QCRG), San Francisco, USA (GRID:grid.266102.1); University of California San Francisco, Quantitative Biosciences Institute, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811); The J. David Gladstone Institutes, Gladstone Institute of Data Science and Biotechnology, San Francisco, USA (GRID:grid.249878.8) (ISNI:0000 0004 0572 7110); University of California, San Francisco, Department of Cellular and Molecular Pharmacology, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811) 
4  QBI Coronavirus Research Group (QCRG), San Francisco, USA (GRID:grid.266102.1); University of California San Francisco, Quantitative Biosciences Institute, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811); University of California, San Francisco, Department of Pharmaceutical Chemistry, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811) 
5  The J. David Gladstone Institutes, Gladstone Institute of Virology, San Francisco, USA (GRID:grid.249878.8) (ISNI:0000 0004 0572 7110); QBI Coronavirus Research Group (QCRG), San Francisco, USA (GRID:grid.249878.8); University of California San Francisco, Quantitative Biosciences Institute, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811); University of California, San Francisco, Department of Medicine, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811); Chan-Zuckerberg Biohub, San Francisco, USA (GRID:grid.499295.a) (ISNI:0000 0004 9234 0175) 
6  Stanford University, Department of Biology, Stanford, USA (GRID:grid.168010.e) (ISNI:0000000419368956) 
7  QBI Coronavirus Research Group (QCRG), San Francisco, USA (GRID:grid.168010.e); University of California San Francisco, Quantitative Biosciences Institute, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811); University of California, San Francisco, Department of Pharmaceutical Chemistry, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811) 
8  QBI Coronavirus Research Group (QCRG), San Francisco, USA (GRID:grid.168010.e); University of California San Francisco, Quantitative Biosciences Institute, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811); The J. David Gladstone Institutes, Gladstone Institute of Data Science and Biotechnology, San Francisco, USA (GRID:grid.249878.8) (ISNI:0000 0004 0572 7110); University of California, San Francisco, Department of Cellular and Molecular Pharmacology, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811) 
Publication year
2022
Publication date
2022
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-022-32758-3
ProQuest document ID
2711639799
Copyright
© The Author(s) 2022. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.