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Structure paper

TitleA conserved glutathione binding site in poliovirus is a target for antivirals and vaccine stabilisation.
Journal, issue, pagesCommun Biol, Vol. 5, Issue 1, Page 1293, Year 2022
Publish dateNov 25, 2022
AuthorsMohammad W Bahar / Veronica Nasta / Helen Fox / Lee Sherry / Keith Grehan / Claudine Porta / Andrew J Macadam / Nicola J Stonehouse / David J Rowlands / Elizabeth E Fry / David I Stuart /
PubMed AbstractStrategies to prevent the recurrence of poliovirus (PV) after eradication may utilise non-infectious, recombinant virus-like particle (VLP) vaccines. Despite clear advantages over inactivated or ...Strategies to prevent the recurrence of poliovirus (PV) after eradication may utilise non-infectious, recombinant virus-like particle (VLP) vaccines. Despite clear advantages over inactivated or attenuated virus vaccines, instability of VLPs can compromise their immunogenicity. Glutathione (GSH), an important cellular reducing agent, is a crucial co-factor for the morphogenesis of enteroviruses, including PV. We report cryo-EM structures of GSH bound to PV serotype 3 VLPs showing that it can enhance particle stability. GSH binds the positively charged pocket at the interprotomer interface shown recently to bind GSH in enterovirus F3 and putative antiviral benzene sulphonamide compounds in other enteroviruses. We show, using high-resolution cryo-EM, the binding of a benzene sulphonamide compound with a PV serotype 2 VLP, consistent with antiviral activity through over-stabilizing the interprotomer pocket, preventing the capsid rearrangements necessary for viral infection. Collectively, these results suggest GSH or an analogous tight-binding antiviral offers the potential for stabilizing VLP vaccines.
External linksCommun Biol / PubMed:36434067 / PubMed Central
MethodsEM (single particle)
Resolution1.88 - 2.6 Å
Structure data

15725

8ayx

EMDB-15725, PDB-8ayx:
Poliovirus type 3 (strain Saukett) stabilised virus-like particle (PV3 SC8) in complex with GSH and GPP3
Method: EM (single particle) / Resolution: 2.5 Å

15726

8ayy

EMDB-15726, PDB-8ayy:
Poliovirus type 3 (strain Saukett) stabilised virus-like particle (PV3 SC8) in complex with GSH and Pleconaril
Method: EM (single particle) / Resolution: 2.6 Å

15727

8ayz

EMDB-15727, PDB-8ayz:
Poliovirus type 2 (strain MEF-1) virus-like particle in complex with capsid binder compound 17
Method: EM (single particle) / Resolution: 1.88 Å

Chemicals

ChemComp-YM2:
1-[(3S)-5-[4-[(E)-ETHOXYIMINOMETHYL]PHENOXY]-3-METHYL-PENTYL]-3-PYRIDIN-4-YL-IMIDAZOLIDIN-2-ONE

ChemComp-GSH:
GLUTATHIONE / Glutathione

ChemComp-W11:
3-{3,5-DIMETHYL-4-[3-(3-METHYL-ISOXAZOL-5-YL)-PROPOXY]-PHENYL}-5-TRIFLUOROMETHYL-[1,2,4]OXADIAZOLE / antivirus*YM / Pleconaril

ChemComp-SPH:
SPHINGOSINE / Sphingosine

ChemComp-FHK:
4-[[4-[1,3-bis(oxidanylidene)isoindol-2-yl]phenyl]sulfonylamino]benzoic acid

ChemComp-HOH:
WATER / Water

Source
  • human poliovirus 3
  • human poliovirus 2
KeywordsVIRUS LIKE PARTICLE / Capsid protein / Glutathione / inhibitor / complex

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