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- EMDB-9828: The cryo-EM structure of HAV bound to a neutralizing antibody-F6 -

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Basic information

Entry
Database: EMDB / ID: EMD-9828
TitleThe cryo-EM structure of HAV bound to a neutralizing antibody-F6
Map datamap of F6_Fab_HAV complex
Sample
  • Complex: Human hepatitis A virus and antibody-F6
    • Complex: antibody-F6
      • Protein or peptide: FAB Light ChainFragment antigen-binding
      • Protein or peptide: FAB Heavy ChainFragment antigen-binding
    • Virus: Human hepatitis A virus
      • Protein or peptide: VP1
      • Protein or peptide: VP2
      • Protein or peptide: VP3
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 cell cytoplasmic vesicle membrane / host multivesicular body / : / nucleoside-triphosphate phosphatase / protein complex oligomerization ...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 cell cytoplasmic vesicle membrane / host multivesicular body / : / nucleoside-triphosphate phosphatase / protein complex oligomerization / monoatomic ion channel activity / RNA helicase activity / symbiont entry into host cell / RNA-directed RNA polymerase / viral RNA genome replication / cysteine-type endopeptidase activity / RNA-dependent RNA polymerase activity / DNA-templated transcription / virion attachment to host cell / structural molecule activity / proteolysis / RNA binding / ATP binding / membrane
Similarity search - Function
: / 2B protein soluble domain / Hepatitis A virus, protein VP1-2A / Hepatitis A virus viral protein VP / Helicase/polymerase/peptidase polyprotein, Calicivirus-type / Picornavirales 3C/3C-like protease domain / Picornavirales 3C/3C-like protease domain profile. / Peptidase C3A/C3B, picornaviral / 3C cysteine protease (picornain 3C) / Picornavirus capsid ...: / 2B protein soluble domain / Hepatitis A virus, protein VP1-2A / Hepatitis A virus viral protein VP / Helicase/polymerase/peptidase polyprotein, Calicivirus-type / Picornavirales 3C/3C-like protease domain / Picornavirales 3C/3C-like protease domain profile. / Peptidase C3A/C3B, picornaviral / 3C cysteine protease (picornain 3C) / 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 / 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
Similarity search - Domain/homology
Biological speciesMus musculus (house mouse) / Human hepatitis A virus Hu/Australia/HM175/1976 / Human hepatitis A virus
Methodsingle particle reconstruction / cryo EM / Resolution: 3.68 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, 3 items
OrganizationGrant numberCountry
National Science Foundation (China)31570717 China
National Science Foundation (China)31370735 China
National Science Foundation (China)31800145 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 18, 2019-
Header (metadata) releaseMar 18, 2020-
Map releaseMar 18, 2020-
UpdateMar 18, 2020-
Current statusMar 18, 2020Processing site: PDBj / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.008
  • Imaged by UCSF Chimera
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  • Surface view colored by radius
  • Surface level: 0.008
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-6jhr
  • Surface level: 0.008
  • Imaged by UCSF Chimera
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  • Simplified surface model + fitted atomic model
  • Atomic modelsPDB-6jhr
  • Imaged by Jmol
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_9828.png

Downloads & links

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Map

FileDownload / File: emd_9828.map.gz / Format: CCP4 / Size: 193.2 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationmap of F6_Fab_HAV complex
Voxel sizeX=Y=Z: 1.35 Å
Density
Contour LevelBy AUTHOR: 0.006 / Movie #1: 0.008
Minimum - Maximum-0.037005812 - 0.0940222
Average (Standard dev.)0.000719891 (±0.0063448227)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin-186-186-186
Dimensions370370370
Spacing370370370
CellA=B=C: 499.5 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.351.351.35
M x/y/z370370370
origin x/y/z0.0000.0000.000
length x/y/z499.500499.500499.500
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS-186-186-186
NC/NR/NS370370370
D min/max/mean-0.0370.0940.001

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Supplemental data

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Sample components

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Entire : Human hepatitis A virus and antibody-F6

EntireName: Human hepatitis A virus and antibody-F6
Components
  • Complex: Human hepatitis A virus and antibody-F6
    • Complex: antibody-F6
      • Protein or peptide: FAB Light ChainFragment antigen-binding
      • Protein or peptide: FAB Heavy ChainFragment antigen-binding
    • Virus: Human hepatitis A virus
      • Protein or peptide: VP1
      • Protein or peptide: VP2
      • Protein or peptide: VP3

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Supramolecule #1: Human hepatitis A virus and antibody-F6

SupramoleculeName: Human hepatitis A virus and antibody-F6 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all

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Supramolecule #3: antibody-F6

SupramoleculeName: antibody-F6 / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #4-#5
Source (natural)Organism: Mus musculus (house mouse)

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Supramolecule #2: Human hepatitis A virus

SupramoleculeName: Human hepatitis A virus / type: virus / ID: 2 / Parent: 1 / Macromolecule list: #1-#3 / NCBI-ID: 208726 / Sci species name: Human hepatitis A virus / Virus type: VIRION / Virus isolate: STRAIN / Virus enveloped: No / Virus empty: No

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Macromolecule #1: VP1

MacromoleculeName: VP1 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Human hepatitis A virus Hu/Australia/HM175/1976
Molecular weightTheoretical: 30.820629 KDa
SequenceString: VGDDSGGFST TVSTEQNVPD PQVGITTMRD LKGKANRGKM DVSGVQAPVG AITTIEDPVL AKKVPETFPE LKPGESRHTS DHMSIYKFM GRSHFLCTFT FNSNNKEYTF PITLSSTSNP PHGLPSTLRW FFNLFQLYRG PLDLTIIITG ATDVDGMAWF T PVGLAVDT ...String:
VGDDSGGFST TVSTEQNVPD PQVGITTMRD LKGKANRGKM DVSGVQAPVG AITTIEDPVL AKKVPETFPE LKPGESRHTS DHMSIYKFM GRSHFLCTFT FNSNNKEYTF PITLSSTSNP PHGLPSTLRW FFNLFQLYRG PLDLTIIITG ATDVDGMAWF T PVGLAVDT PWVEKESALQ IDYKTALGAV RFNTRRTGNI QIRLPWYSYL YAVSGALDGL GDKTDSTFGL VSIQIANYNH SD EYLSFSC YLSVTEQSEF YFPRAPLNSN AMLSTESMMS R

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Macromolecule #2: VP2

MacromoleculeName: VP2 / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Human hepatitis A virus Hu/Australia/HM175/1976
Molecular weightTheoretical: 24.898172 KDa
SequenceString: DIEEEQMIQS VDRTAVTGAS YFTSVDQSSV HTAEVGSHQI EPLKTSVDKP GSKKTQGEKF FLIHSARWLT THALFHEVAK LDVVKLLYN EQFAVQGLLR YHTYARFGIE IQVQINPTPF QQGGLICAMV PGDQSYGSIA SLTVYPHGLL NCNINNVVRI K VPFIYTRG ...String:
DIEEEQMIQS VDRTAVTGAS YFTSVDQSSV HTAEVGSHQI EPLKTSVDKP GSKKTQGEKF FLIHSARWLT THALFHEVAK LDVVKLLYN EQFAVQGLLR YHTYARFGIE IQVQINPTPF QQGGLICAMV PGDQSYGSIA SLTVYPHGLL NCNINNVVRI K VPFIYTRG AYHFKDPQYP VWELTIRVWS ELNIGTGTSA YTSLNVLARF TDLELHGLTP LSTQ

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Macromolecule #3: VP3

MacromoleculeName: VP3 / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Human hepatitis A virus Hu/Australia/HM175/1976
Molecular weightTheoretical: 27.835693 KDa
SequenceString: MMRNETRVST TENVVNLSNY EDARAKMSFA LDQEDWKSDP SQGGGIKITH FTTWTSIPTL AAQFPFNASD SVGQQIKVIP VDPYFFQMT NTNPDQKCIT ALASICQMFC FWRGDLVFDF QVFPTKYHSG RLLFCFVPGN ELIDVTGITL KQATTAPCAV M DIAGVQST ...String:
MMRNETRVST TENVVNLSNY EDARAKMSFA LDQEDWKSDP SQGGGIKITH FTTWTSIPTL AAQFPFNASD SVGQQIKVIP VDPYFFQMT NTNPDQKCIT ALASICQMFC FWRGDLVFDF QVFPTKYHSG RLLFCFVPGN ELIDVTGITL KQATTAPCAV M DIAGVQST LRFRVPWISD TPYRVNRYTK EAHQKGEYTA IGKLIVYCYN RLTSPSNVAH HVRVNVYLSA INLECFAPLY HA MDVTTQ

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Macromolecule #4: FAB Light Chain

MacromoleculeName: FAB Light Chain / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 23.788209 KDa
SequenceString: DIVLTQSPAI MSASPGERVT MTCSAHQYVS YMHWYQQKSG TSPKRWIYDT SRLADAIPQR FSGRGSGTSY SLTISSMEAE DAATYYCQQ WQSNPYTFGG GTKLEIKRAD AAPTVSIFPP SSEQLTSGGA SVVCFLNNFY PKDINVKWKI DGSERQNGVL N SWTDQDSK ...String:
DIVLTQSPAI MSASPGERVT MTCSAHQYVS YMHWYQQKSG TSPKRWIYDT SRLADAIPQR FSGRGSGTSY SLTISSMEAE DAATYYCQQ WQSNPYTFGG GTKLEIKRAD AAPTVSIFPP SSEQLTSGGA SVVCFLNNFY PKDINVKWKI DGSERQNGVL N SWTDQDSK DSTYSMSSTL TLTKDEYERH NSYTCEATHK TSTSPIVKSF NRNEC

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Macromolecule #5: FAB Heavy Chain

MacromoleculeName: FAB Heavy Chain / type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 24.208324 KDa
SequenceString: EVKLVESGGG LVKPGGSLKL SCAASMYNFQ HYGMSWVRQT PEKRLEWVAT IQTNATYTYY PDSVKGRFTI SRDNARNILY LQMSSLRSG DTAMYYCARR DNIECHYYFD YWGQGTTLTV SSPKTTPPSV YPLAPASAST AASMVTLGCL VKGYFPEPVT V TWNSGSLS ...String:
EVKLVESGGG LVKPGGSLKL SCAASMYNFQ HYGMSWVRQT PEKRLEWVAT IQTNATYTYY PDSVKGRFTI SRDNARNILY LQMSSLRSG DTAMYYCARR DNIECHYYFD YWGQGTTLTV SSPKTTPPSV YPLAPASAST AASMVTLGCL VKGYFPEPVT V TWNSGSLS SGVHTFPAVL QSDLYTLSSS VTVPSSTWPS ETVTCNVAHP ASSTKVDKKI VPR

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy
Image recordingFilm or detector model: GATAN K2 BASE (4k x 4k) / Average electron dose: 1.3 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: EMDB MAP
EMDB ID:

6688

Initial angle assignmentType: RANDOM ASSIGNMENT
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.68 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: PHENIX / Number images used: 7245

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