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; Nevan J Krogan

doi:10.1038/s41467-022-32758-3

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

Nat Commun. 2022 Sep 8;13(1):5282. doi: 10.1038/s41467-022-32758-3.

Authors

Christine E Peters^#¹, Ursula Schulze-Gahmen^#^{2

3

4}, Manon Eckhardt^{3

4

5

6}, Gwendolyn M Jang^{3

4

5

6}, Jiewei Xu^{3

4

5

6}, Ernst H Pulido^{3

4

5

6}, Conner Bardine^{3

4

7}, Charles S Craik^{3

4

7}, Melanie Ott^{2

3

4

8

9}, Or Gozani¹⁰, Kliment A Verba^{11

12

13}, Ruth Hüttenhain^{14

15

16

17}, Jan E Carette¹⁸, Nevan J Krogan^{19

20

21

22}

Affiliations

¹ Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA.
² Gladstone Institute of Virology, The J. David Gladstone Institutes, San Francisco, CA, USA.
³ QBI Coronavirus Research Group (QCRG), San Francisco, CA, USA.
⁴ Quantitative Biosciences Institute, University of California San Francisco, San Francisco, CA, USA.
⁵ Gladstone Institute of Data Science and Biotechnology, The J. David Gladstone Institutes, San Francisco, CA, USA.
⁶ Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA, USA.
⁷ Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA, USA.
⁸ Department of Medicine, University of California, San Francisco, San Francisco, CA, USA.
⁹ Chan-Zuckerberg Biohub, San Francisco, CA, USA.
¹⁰ Department of Biology, Stanford University, Stanford, CA, USA.
¹¹ QBI Coronavirus Research Group (QCRG), San Francisco, CA, USA. Kliment.Verba@ucsf.edu.
¹² Quantitative Biosciences Institute, University of California San Francisco, San Francisco, CA, USA. Kliment.Verba@ucsf.edu.
¹³ Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA, USA. Kliment.Verba@ucsf.edu.
¹⁴ QBI Coronavirus Research Group (QCRG), San Francisco, CA, USA. Ruth.Huttenhain@ucsf.edu.
¹⁵ Quantitative Biosciences Institute, University of California San Francisco, San Francisco, CA, USA. Ruth.Huttenhain@ucsf.edu.
¹⁶ Gladstone Institute of Data Science and Biotechnology, The J. David Gladstone Institutes, San Francisco, CA, USA. Ruth.Huttenhain@ucsf.edu.
¹⁷ Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA, USA. Ruth.Huttenhain@ucsf.edu.
¹⁸ Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA. carette@stanford.edu.
¹⁹ QBI Coronavirus Research Group (QCRG), San Francisco, CA, USA. nevan.krogan@ucsf.edu.
²⁰ Quantitative Biosciences Institute, University of California San Francisco, San Francisco, CA, USA. nevan.krogan@ucsf.edu.
²¹ Gladstone Institute of Data Science and Biotechnology, The J. David Gladstone Institutes, San Francisco, CA, USA. nevan.krogan@ucsf.edu.
²² Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA, USA. nevan.krogan@ucsf.edu.

^# Contributed equally.

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.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Antigens, Viral / metabolism
Endopeptidases / metabolism
Enterovirus Infections*
Enterovirus* / genetics
Histone Methyltransferases / metabolism
Humans
Peptide Hydrolases / metabolism

Substances

Antigens, Viral
Histone Methyltransferases
SETD3 protein, human
Endopeptidases
Peptide Hydrolases

Abstract

Publication types

MeSH terms

Substances

Grants and funding