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- Title
Structure-function analysis of enterovirus protease 2A in complex with its essential host factor SETD3.
- Authors
Peters, Christine E.; Schulze-Gahmen, Ursula; Eckhardt, Manon; Jang, Gwendolyn M.; Xu, Jiewei; Pulido, Ernst H.; Bardine, Conner; Craik, Charles S.; Ott, Melanie; Gozani, Or; Verba, Kliment A.; Hüttenhain, Ruth; Carette, Jan E.; Krogan, Nevan J.
- 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.
- Subjects
ENTEROVIRUS diseases; MICROFILAMENT proteins; ENTEROVIRUSES; VIRAL replication; HISTIDINE; ACTIN; METHYLTRANSFERASES
- Publication
Nature Communications, 2022, Vol 13, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-022-32758-3