Structure-function analysis of enterovirus protease 2A in complex with its essential host factor SETD3.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
08 09 2022
08 09 2022
Historique:
received:
14
06
2022
accepted:
16
08
2022
entrez:
8
9
2022
pubmed:
9
9
2022
medline:
14
9
2022
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 36075902
doi: 10.1038/s41467-022-32758-3
pii: 10.1038/s41467-022-32758-3
pmc: PMC9453702
doi:
Substances chimiques
Antigens, Viral
0
Histone Methyltransferases
EC 2.1.1.-
SETD3 protein, human
EC 2.1.1.43
Endopeptidases
EC 3.4.-
Peptide Hydrolases
EC 3.4.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
5282Subventions
Organisme : NIAID NIH HHS
ID : U19 AI171421
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI130123
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI141970
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI153169
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM145460
Pays : United States
Organisme : NIAID NIH HHS
ID : U19 AI135990
Pays : United States
Organisme : NIGMS NIH HHS
ID : R35 GM139569
Pays : United States
Organisme : NIAID NIH HHS
ID : P50 AI150476
Pays : United States
Organisme : NIAID NIH HHS
ID : U19 AI171110
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI140186
Pays : United States
Informations de copyright
© 2022. The Author(s).
Références
J Comput Chem. 2004 Oct;25(13):1605-12
pubmed: 15264254
Elife. 2019 Feb 20;8:
pubmed: 30785395
Protein Sci. 2021 Jan;30(1):70-82
pubmed: 32881101
Nucleic Acids Res. 2019 Jan 8;47(D1):D442-D450
pubmed: 30395289
Elife. 2018 Dec 11;7:
pubmed: 30526847
Nat Rev Microbiol. 2018 Jun;16(6):368-381
pubmed: 29626210
J Virol. 2009 Nov;83(22):11940-9
pubmed: 19740986
Nat Methods. 2017 Aug;14(8):793-796
pubmed: 28671674
Acta Crystallogr D Biol Crystallogr. 2011 Apr;67(Pt 4):235-42
pubmed: 21460441
Science. 2018 Mar 9;359(6380):1170-1177
pubmed: 29439025
J Biol Chem. 2009 May 29;284(22):15026-37
pubmed: 19359250
Nat Microbiol. 2019 Dec;4(12):2523-2537
pubmed: 31527793
Nat Methods. 2014 Jan;11(1):63-5
pubmed: 24213166
Antimicrob Agents Chemother. 2009 May;53(5):1850-7
pubmed: 19237651
mBio. 2019 Feb 12;10(1):
pubmed: 30755512
Nature. 2011 Dec 21;481(7381):365-70
pubmed: 22190034
PLoS Pathog. 2019 Aug 5;15(8):e1007962
pubmed: 31381608
J Struct Biol. 2015 Nov;192(2):216-21
pubmed: 26278980
Nat Methods. 2017 Mar;14(3):290-296
pubmed: 28165473
Elife. 2016 Sep 26;5:
pubmed: 27669148
J Gen Virol. 2001 Feb;82(Pt 2):397-408
pubmed: 11161279
Bioinformatics. 2014 Sep 1;30(17):2524-6
pubmed: 24794931
Nat Protoc. 2014 Sep;9(9):2100-22
pubmed: 25101824
Antimicrob Agents Chemother. 2012 Oct;56(10):5149-56
pubmed: 22825118
Cell. 2018 Feb 22;172(5):1007-1021.e17
pubmed: 29474905
Nat Rev Drug Discov. 2018 Jan;17(1):35-56
pubmed: 28935918
Rev Med Virol. 2016 Jul;26(4):251-67
pubmed: 27145174
Nat Biotechnol. 2008 Dec;26(12):1367-72
pubmed: 19029910
Methods. 2011 Jan;53(1):13-9
pubmed: 20708689
mBio. 2013 Apr 09;4(2):e00098-13
pubmed: 23572552
Nature. 2011 Dec 21;481(7381):371-5
pubmed: 22190037
Nat Rev Drug Discov. 2021 Apr;20(4):265-286
pubmed: 33469207
PLoS Pathog. 2013;9(6):e1003401
pubmed: 23762027
PLoS One. 2009 Aug 06;4(8):e6529
pubmed: 19657394
J Mol Biol. 2007 Sep 21;372(3):774-97
pubmed: 17681537
Curr Protoc Bioinformatics. 2012 Sep;Chapter 8:Unit8.15
pubmed: 22948729
J Struct Biol. 2016 Jul;195(1):93-9
pubmed: 27108186
Acta Crystallogr D Biol Crystallogr. 2010 Apr;66(Pt 4):486-501
pubmed: 20383002
ChemMedChem. 2021 Sep 6;16(17):2695-2702
pubmed: 34032009
J Virol. 2012 Nov;86(21):11595-607
pubmed: 22896614
Virology. 2006 Feb 20;345(2):346-57
pubmed: 16297952
Nat Methods. 2014 Aug;11(8):783-784
pubmed: 25075903
J Mol Evol. 2002 Feb;54(2):156-65
pubmed: 11821909
EMBO J. 2012 Feb 1;31(3):754-66
pubmed: 22124328
Acta Crystallogr D Struct Biol. 2019 Oct 1;75(Pt 10):861-877
pubmed: 31588918
Genetics. 1988 Nov;120(3):621-3
pubmed: 2852134
Antimicrob Agents Chemother. 2013 Jul;57(7):3358-68
pubmed: 23650168
Acta Crystallogr D Struct Biol. 2018 Jun 1;74(Pt 6):519-530
pubmed: 29872003
Nat Chem Biol. 2020 Feb;16(2):214-222
pubmed: 31819273
Nat Rev Genet. 2020 Jun;21(6):339-354
pubmed: 32060427
Mol Cell. 2018 Sep 6;71(5):653-673
pubmed: 30193094
Mol Syst Biol. 2021 Jan;17(1):e8792
pubmed: 33434350
Nat Methods. 2017 Apr;14(4):331-332
pubmed: 28250466
PLoS One. 2010 Oct 27;5(10):e13687
pubmed: 21060866
Science. 2009 Apr 3;324(5923):55-9
pubmed: 19213880
Mol Cell Proteomics. 2006 Jan;5(1):144-56
pubmed: 16219938
Nature. 2019 Jan;565(7739):372-376
pubmed: 30626964
Curr Opin Chem Biol. 2020 Feb;54:54-62
pubmed: 31838273
Nature. 2020 Jul;583(7816):459-468
pubmed: 32353859
Nat Methods. 2011 Jan;8(1):70-3
pubmed: 21131968
J Biol Chem. 1993 Sep 15;268(26):19200-3
pubmed: 8396129