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

Christine E. Peters, Ursula Schulze-Gahmen, Manon Eckhardt, Gwendolyn M. Jang, Jiewei Xu, Ernst H. Pulido, Conner Bardine, Charles S. Craik, Melanie Ott, Or Gozani, Kliment A. Verba (), Ruth Hüttenhain (), Jan E. Carette () and Nevan J. Krogan ()
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Christine E. Peters: Stanford University School of Medicine
Ursula Schulze-Gahmen: The J. David Gladstone Institutes
Manon Eckhardt: QBI Coronavirus Research Group (QCRG)
Gwendolyn M. Jang: QBI Coronavirus Research Group (QCRG)
Jiewei Xu: QBI Coronavirus Research Group (QCRG)
Ernst H. Pulido: QBI Coronavirus Research Group (QCRG)
Conner Bardine: QBI Coronavirus Research Group (QCRG)
Charles S. Craik: QBI Coronavirus Research Group (QCRG)
Melanie Ott: The J. David Gladstone Institutes
Or Gozani: Stanford University
Kliment A. Verba: QBI Coronavirus Research Group (QCRG)
Ruth Hüttenhain: QBI Coronavirus Research Group (QCRG)
Jan E. Carette: Stanford University School of Medicine
Nevan J. Krogan: QBI Coronavirus Research Group (QCRG)

Nature Communications, 2022, vol. 13, issue 1, 1-15

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-32758-3

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