A pH-dependent cluster of charges in a conserved cryptic pocket on flaviviral envelopes.
benzene-mapping
constant-pH simulations
cryptic pockets
enveloped virus
flavivirus
infectious disease
microbiology
molecular biophysics
molecular dynamics simulations
none
structural biology
Journal
eLife
ISSN: 2050-084X
Titre abrégé: Elife
Pays: England
ID NLM: 101579614
Informations de publication
Date de publication:
05 05 2023
05 05 2023
Historique:
received:
04
08
2022
accepted:
18
04
2023
medline:
8
5
2023
pubmed:
5
5
2023
entrez:
5
5
2023
Statut:
epublish
Résumé
Flaviviruses are enveloped viruses which include human pathogens that are predominantly transmitted by mosquitoes and ticks. Some, such as dengue virus, exhibit the phenomenon of antibody-dependent enhancement (ADE) of disease, making vaccine-based routes of fighting infections problematic. The pH-dependent conformational change of the envelope (E) protein required for fusion between the viral and endosomal membranes is an attractive point of inhibition by antivirals as it has the potential to diminish the effects of ADE. We examined six flaviviruses by employing large-scale molecular dynamics (MD) simulations of raft systems that represent a substantial portion of the flaviviral envelope. We utilised a benzene-mapping approach that led to a discovery of shared hotspots and conserved cryptic sites. A cryptic pocket previously shown to bind a detergent molecule exhibited strain-specific characteristics. An alternative conserved cryptic site at the E protein domain interfaces showed a consistent dynamic behaviour across flaviviruses and contained a conserved cluster of ionisable residues. Constant-pH simulations revealed cluster and domain-interface disruption under low pH conditions. Based on this, we propose a cluster-dependent mechanism that addresses inconsistencies in the histidine-switch hypothesis and highlights the role of cluster protonation in orchestrating the domain dissociation pivotal for the formation of the fusogenic trimer.
Identifiants
pubmed: 37144875
doi: 10.7554/eLife.82447
pii: 82447
pmc: PMC10162804
doi:
pii:
Substances chimiques
Histidine
4QD397987E
Viral Envelope Proteins
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
© 2023, Zuzic et al.
Déclaration de conflit d'intérêts
LZ, JM, GA, JW, PB No competing interests declared
Références
Nature. 2016 Aug 4;536(7614):48-53
pubmed: 27338953
Elife. 2015 Jun 30;4:e08347
pubmed: 26126267
Biopolymers. 1983 Dec;22(12):2577-637
pubmed: 6667333
J Infect Dis. 1979 Oct;140(4):527-33
pubmed: 117061
Nucleic Acids Res. 2016 Jul 8;44(W1):W344-50
pubmed: 27166375
J Comput Chem. 2005 Dec;26(16):1668-88
pubmed: 16200636
J Chem Inf Model. 2012 Aug 27;52(8):2236-44
pubmed: 22770357
J Virol. 2010 Aug;84(16):8353-8
pubmed: 20519400
PLoS Pathog. 2019 Sep 19;15(9):e1007996
pubmed: 31536610
Arch Virol. 2013 Jul;158(7):1445-59
pubmed: 23471635
Cell Chem Biol. 2018 Aug 16;25(8):1006-1016.e8
pubmed: 29937406
J Mol Graph. 1996 Feb;14(1):33-8, 27-8
pubmed: 8744570
Virology. 2008 Aug 15;378(1):193-9
pubmed: 18571214
J Mol Biol. 1993 Dec 5;234(3):779-815
pubmed: 8254673
J Virol. 2009 Dec;83(23):12631-5
pubmed: 19776132
Proc Natl Acad Sci U S A. 2013 Apr 23;110(17):6795-9
pubmed: 23569243
Expert Rev Vaccines. 2017 Jul;16(7):1-13
pubmed: 28590795
Nat Commun. 2020 Jun 19;11(1):3112
pubmed: 32561757
PLoS Pathog. 2012;8(3):e1002584
pubmed: 22457619
Nature. 2013 Apr 25;496(7446):504-7
pubmed: 23563266
PLoS Comput Biol. 2009 Jul;5(7):e1000435
pubmed: 19593374
Physiology (Bethesda). 2007 Feb;22:30-9
pubmed: 17289928
J Virol. 2013 Jul;87(13):7585-92
pubmed: 23637405
PLoS Negl Trop Dis. 2012;6(8):e1760
pubmed: 22880140
J Gen Virol. 2008 Feb;89(Pt 2):474-484
pubmed: 18198378
Bioinformatics. 2011 Dec 1;27(23):3276-85
pubmed: 21967761
PLoS One. 2018 Dec 31;13(12):e0210122
pubmed: 30596764
Nat Microbiol. 2019 May;4(5):854-863
pubmed: 30833735
J Am Chem Soc. 2016 Nov 2;138(43):14257-14263
pubmed: 27726386
J Virol. 2012 Feb;86(4):2337-46
pubmed: 22156523
J Virol. 2006 Nov;80(22):11000-8
pubmed: 16943291
J Comput Chem. 2008 Aug;29(11):1859-65
pubmed: 18351591
PLoS Pathog. 2010 Feb 12;6(2):e1000790
pubmed: 20168989
Structure. 2019 Feb 5;27(2):253-267.e8
pubmed: 30471923
J Biol Chem. 2012 Nov 23;287(48):40525-34
pubmed: 23035113
Protein Sci. 2021 Jan;30(1):70-82
pubmed: 32881101
J Med Chem. 2010 Aug 12;53(15):5858-67
pubmed: 20684613
Protein Sci. 2004 Oct;13(10):2793-805
pubmed: 15388865
J Gen Virol. 1990 Aug;71 ( Pt 8):1845-50
pubmed: 2167941
Nat Biotechnol. 1996 May;14(5):595-9
pubmed: 9630949
Nat Rev Drug Discov. 2017 Aug;16(8):565-586
pubmed: 28473729
J Virol. 2006 Dec;80(23):11467-74
pubmed: 16987985
Science. 2016 Apr 22;352(6284):467-70
pubmed: 27033547
Proc Natl Acad Sci U S A. 2003 Jun 10;100(12):6986-91
pubmed: 12759475
Amino Acids. 2011 Nov;41(5):1159-63
pubmed: 19882217
Curr Opin Virol. 2019 Jun;36:1-8
pubmed: 30844538
J Virol. 2005 Jan;79(2):1223-31
pubmed: 15613349
Cell Rep. 2019 Jan 8;26(2):438-446.e5
pubmed: 30625326
PLoS Pathog. 2013 Feb;9(2):e1003157
pubmed: 23459315
J Chem Theory Comput. 2020 Sep 8;16(9):5948-5959
pubmed: 32786908
Structure. 2004 Sep;12(9):1607-18
pubmed: 15341726
J Chem Theory Comput. 2019 May 14;15(5):3331-3343
pubmed: 30998331
Nat Biotechnol. 2007 Jan;25(1):71-5
pubmed: 17211405
J Gen Virol. 2009 Sep;90(Pt 9):2097-106
pubmed: 19494052
Virology. 1994 Jan;198(1):109-17
pubmed: 8259646
Biophys Chem. 1997 Feb 28;64(1-3):211-24
pubmed: 9127946
J Virol. 2014 Oct;88(20):12041-54
pubmed: 25122799
PLoS One. 2015 Apr 27;10(4):e0125293
pubmed: 25915903
Bioinformatics. 2009 May 1;25(9):1189-91
pubmed: 19151095
J Cell Biol. 2008 Oct 20;183(2):353-61
pubmed: 18936253
Nature. 2004 Jan 22;427(6972):313-9
pubmed: 14737159
BMC Bioinformatics. 2004 Aug 19;5:113
pubmed: 15318951
Proteins. 2006 Nov 15;65(3):712-25
pubmed: 16981200
Nat Struct Mol Biol. 2013 Jan;20(1):105-10
pubmed: 23241927
J Comput Chem. 2004 Dec;25(16):2038-48
pubmed: 15481090
ACS Infect Dis. 2019 Mar 8;5(3):460-472
pubmed: 30608640
Acc Chem Res. 2020 Mar 17;53(3):654-661
pubmed: 32134250
Annu Rev Phys Chem. 2000;51:129-52
pubmed: 11031278
Structure. 2018 Sep 4;26(9):1169-1177.e3
pubmed: 29958768
J Gen Virol. 2001 Aug;82(Pt 8):1867-1876
pubmed: 11457992
J Chem Theory Comput. 2022 Oct 11;18(10):6148-6160
pubmed: 36128977
Virology. 2015 May;479-480:498-507
pubmed: 25866377
Cell Host Microbe. 2016 May 11;19(5):696-704
pubmed: 27158114
PLoS Pathog. 2021 Feb 23;17(2):e1009331
pubmed: 33621239
J Phys Chem Lett. 2016 Sep 1;7(17):3452-7
pubmed: 27532490
Virus Res. 2013 Jun;174(1-2):78-87
pubmed: 23517753
J Chem Phys. 2007 Jan 7;126(1):014101
pubmed: 17212484
J Virol. 2013 Jul;87(13):7700-7
pubmed: 23637416
J Comput Chem. 2013 Sep 30;34(25):2135-45
pubmed: 23832629
J Med Chem. 2006 Dec 14;49(25):7384-92
pubmed: 17149868
Curr Opin Struct Biol. 2002 Feb;12(1):14-20
pubmed: 11839484
J Comput Chem. 2014 Oct 15;35(27):1997-2004
pubmed: 25130509
Nat Commun. 2017 Feb 10;8:14339
pubmed: 28186093
EMBO Rep. 2018 Feb;19(2):206-224
pubmed: 29282215
J Virol. 2001 May;75(9):4268-75
pubmed: 11287576
Proc Natl Acad Sci U S A. 2011 Mar 29;108(13):5260-5
pubmed: 21389271
Nat Commun. 2021 Feb 23;12(1):1238
pubmed: 33623019