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- PDB-6jht: The cryo-EM structure of HAV bound to a neutralizing antibody-F9 -

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Basic information

Entry
Database: PDB / ID: 6jht
TitleThe cryo-EM structure of HAV bound to a neutralizing antibody-F9
Components
  • FAB Heavy Chain
  • FAB Light Chain
  • VP1
  • VP2
  • VP3
KeywordsVIRUS / Icosahedral symmetry / neutralizing antibody / HAV / complex
Function / homology
Function and homology information


host cell mitochondrial outer membrane / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of MAVS activity / ribonucleoside triphosphate phosphatase activity / picornain 3C / T=pseudo3 icosahedral viral capsid / host multivesicular body / host cell cytoplasmic vesicle membrane / nucleoside-triphosphate phosphatase / channel activity / monoatomic ion transmembrane transport ...host cell mitochondrial outer membrane / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of MAVS activity / ribonucleoside triphosphate phosphatase activity / picornain 3C / T=pseudo3 icosahedral viral capsid / host multivesicular body / host cell cytoplasmic vesicle membrane / nucleoside-triphosphate phosphatase / channel activity / monoatomic ion transmembrane transport / RNA helicase activity / symbiont entry into host cell / RNA-directed RNA polymerase / cysteine-type endopeptidase activity / viral RNA genome replication / RNA-directed RNA polymerase activity / DNA-templated transcription / : / virion attachment to host cell / structural molecule activity / proteolysis / RNA binding / ATP binding / membrane
Similarity search - Function
Hepatitis A virus, protein VP1-2A / : / Hepatitis A virus viral protein VP / 2B protein soluble domain / Helicase/polymerase/peptidase polyprotein, Calicivirus-type / Jelly Rolls - #20 / Peptidase C3A/C3B, picornaviral / 3C cysteine protease (picornain 3C) / Picornavirales 3C/3C-like protease domain / Picornavirales 3C/3C-like protease domain profile. ...Hepatitis A virus, protein VP1-2A / : / Hepatitis A virus viral protein VP / 2B protein soluble domain / Helicase/polymerase/peptidase polyprotein, Calicivirus-type / Jelly Rolls - #20 / Peptidase C3A/C3B, picornaviral / 3C cysteine protease (picornain 3C) / Picornavirales 3C/3C-like protease domain / Picornavirales 3C/3C-like protease domain profile. / Picornavirus capsid / picornavirus capsid protein / Helicase, superfamily 3, single-stranded RNA virus / Superfamily 3 helicase of positive ssRNA viruses domain profile. / Helicase, superfamily 3, single-stranded DNA/RNA virus / RNA helicase / Picornavirus/Calicivirus coat protein / Viral coat protein subunit / RNA-directed RNA polymerase, C-terminal domain / Viral RNA-dependent RNA polymerase / Reverse transcriptase/Diguanylate cyclase domain / Jelly Rolls / RNA-directed RNA polymerase, catalytic domain / RdRp of positive ssRNA viruses catalytic domain profile. / Peptidase S1, PA clan, chymotrypsin-like fold / Peptidase S1, PA clan / DNA/RNA polymerase superfamily / Immunoglobulins / Immunoglobulin-like / Sandwich / Mainly Beta
Similarity search - Domain/homology
Biological speciesHuman hepatitis A virus Hu/Australia/HM175/1976
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.79 Å
AuthorsCao, L. / Liu, P. / Yang, P. / Gao, Q. / Li, H. / Sun, Y. / Zhu, L. / Lin, J. / Su, D. / Rao, Z. / Wang, X.
Funding support China, 3items
OrganizationGrant numberCountry
National Science Foundation (China)31570717 China
National Science Foundation (China)31800145 China
National Science Foundation (China)31370735 China
CitationJournal: PLoS Biol / Year: 2019
Title: Structural basis for neutralization of hepatitis A virus informs a rational design of highly potent inhibitors.
Authors: Lei Cao / Pi Liu / Pan Yang / Qiang Gao / Hong Li / Yao Sun / Ling Zhu / Jianping Lin / Dan Su / Zihe Rao / Xiangxi Wang /
Abstract: Hepatitis A virus (HAV), an enigmatic and ancient pathogen, is a major causative agent of acute viral hepatitis worldwide. Although there are effective vaccines, antivirals against HAV infection are ...Hepatitis A virus (HAV), an enigmatic and ancient pathogen, is a major causative agent of acute viral hepatitis worldwide. Although there are effective vaccines, antivirals against HAV infection are still required, especially during fulminant hepatitis outbreaks. A more in-depth understanding of the antigenic characteristics of HAV and the mechanisms of neutralization could aid in the development of rationally designed antiviral drugs targeting HAV. In this paper, 4 new antibodies-F4, F6, F7, and F9-are reported that potently neutralize HAV at 50% neutralizing concentration values (neut50) ranging from 0.1 nM to 0.85 nM. High-resolution cryo-electron microscopy (cryo-EM) structures of HAV bound to F4, F6, F7, and F9, together with results of our previous studies on R10 fragment of antigen binding (Fab)-HAV complex, shed light on the locations and nature of the epitopes recognized by the 5 neutralizing monoclonal antibodies (NAbs). All the epitopes locate within the same patch and are highly conserved. The key structure-activity correlates based on the antigenic sites have been established. Based on the structural data of the single conserved antigenic site and key structure-activity correlates, one promising drug candidate named golvatinib was identified by in silico docking studies. Cell-based antiviral assays confirmed that golvatinib is capable of blocking HAV infection effectively with a 50% inhibitory concentration (IC50) of approximately 1 μM. These results suggest that the single conserved antigenic site from complete HAV capsid is a good antiviral target and that golvatinib could function as a lead compound for anti-HAV drug development.
History
DepositionFeb 19, 2019Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Mar 18, 2020Provider: repository / Type: Initial release
Revision 1.1Nov 13, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / em_admin / pdbx_entry_details / pdbx_modification_feature / pdbx_struct_oper_list
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _em_admin.last_update / _pdbx_struct_oper_list.name / _pdbx_struct_oper_list.symmetry_operation / _pdbx_struct_oper_list.type

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Structure visualization

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  • Biological unit as complete icosahedral assembly
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  • Biological unit as icosahedral pentamer
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  • Biological unit as icosahedral 23 hexamer
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  • Deposited structure unit
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  • Simplified surface model + fitted atomic model
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  • Superimposition on EM map
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Structure viewerMolecule:
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Assembly

Deposited unit
A: VP1
B: VP2
C: VP3
D: FAB Light Chain
E: FAB Heavy Chain


Theoretical massNumber of molelcules
Total (without water)130,6315
Polymers130,6315
Non-polymers00
Water00
1
A: VP1
B: VP2
C: VP3
D: FAB Light Chain
E: FAB Heavy Chain
x 60


Theoretical massNumber of molelcules
Total (without water)7,837,862300
Polymers7,837,862300
Non-polymers00
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
point symmetry operation59
2


  • Idetical with deposited unit
  • icosahedral asymmetric unit
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
A: VP1
B: VP2
C: VP3
D: FAB Light Chain
E: FAB Heavy Chain
x 5


  • icosahedral pentamer
  • 653 kDa, 25 polymers
Theoretical massNumber of molelcules
Total (without water)653,15525
Polymers653,15525
Non-polymers00
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
point symmetry operation4
4
A: VP1
B: VP2
C: VP3
D: FAB Light Chain
E: FAB Heavy Chain
x 6


  • icosahedral 23 hexamer
  • 784 kDa, 30 polymers
Theoretical massNumber of molelcules
Total (without water)783,78630
Polymers783,78630
Non-polymers00
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
point symmetry operation5
5


  • Idetical with deposited unit in distinct coordinate
  • icosahedral asymmetric unit, std point frame
TypeNameSymmetry operationNumber
transform to point frame1
SymmetryPoint symmetry: (Schoenflies symbol: I (icosahedral))

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Components

#1: Protein VP1


Mass: 30820.629 Da / Num. of mol.: 1 / Source method: isolated from a natural source
Source: (natural) Human hepatitis A virus Hu/Australia/HM175/1976
References: UniProt: P08617*PLUS
#2: Protein VP2


Mass: 24898.172 Da / Num. of mol.: 1 / Source method: isolated from a natural source
Source: (natural) Human hepatitis A virus Hu/Australia/HM175/1976
References: UniProt: P08617*PLUS
#3: Protein VP3


Mass: 27835.693 Da / Num. of mol.: 1 / Source method: isolated from a natural source
Source: (natural) Human hepatitis A virus Hu/Australia/HM175/1976
References: UniProt: P08617*PLUS
#4: Antibody FAB Light Chain


Mass: 23391.775 Da / Num. of mol.: 1 / Source method: isolated from a natural source
Source: (natural) Human hepatitis A virus Hu/Australia/HM175/1976
#5: Antibody FAB Heavy Chain


Mass: 23684.768 Da / Num. of mol.: 1 / Source method: isolated from a natural source
Source: (natural) Human hepatitis A virus Hu/Australia/HM175/1976
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

Component
IDNameTypeEntity IDParent-IDSource
1Human hepatitis A virus and antibody-F9COMPLEXall0NATURAL
2Human hepatitis A virusVIRUS#1-#31NATURAL
3antibody-F9COMPLEX#4-#51NATURAL
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
12Human hepatitis A virus208726
23Mus musculus (house mouse)10090
Details of virusEmpty: NO / Enveloped: NO / Isolate: SPECIES / Type: VIRION
Buffer solutionpH: 7
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD
Image recordingElectron dose: 1.3 e/Å2 / Film or detector model: GATAN K2 BASE (4k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.11.1_2575: / Classification: refinement
EM softwareName: PHENIX / Category: 3D reconstruction
CTF correctionType: NONE
3D reconstructionResolution: 3.79 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 3798 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00415042
ELECTRON MICROSCOPYf_angle_d0.78720511
ELECTRON MICROSCOPYf_dihedral_angle_d9.3518855
ELECTRON MICROSCOPYf_chiral_restr0.0532316
ELECTRON MICROSCOPYf_plane_restr0.0072616

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