+Open data
-Basic information
Entry | Database: PDB / ID: 6jhr | ||||||||||||
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Title | The cryo-EM structure of HAV bound to a neutralizing antibody-F6 | ||||||||||||
Components |
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Keywords | VIRUS / 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 cell cytoplasmic vesicle membrane / host multivesicular body / nucleoside-triphosphate phosphatase / protein complex oligomerization / monoatomic ion channel activity ...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 / virus-mediated perturbation of host defense response / DNA-templated transcription / virion attachment to host cell / structural molecule activity / proteolysis / RNA binding / ATP binding / membrane Similarity search - Function | ||||||||||||
Biological species | Human hepatitis A virus Hu/Australia/HM175/1976 Mus musculus (house mouse) | ||||||||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.68 Å | ||||||||||||
Authors | Cao, 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
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Citation | Journal: 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 |
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-Structure visualization
Movie |
Movie viewer |
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Structure viewer | Molecule: MolmilJmol/JSmol |
-Downloads & links
-Download
PDBx/mmCIF format | 6jhr.cif.gz | 207.6 KB | Display | PDBx/mmCIF format |
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PDB format | pdb6jhr.ent.gz | 171.3 KB | Display | PDB format |
PDBx/mmJSON format | 6jhr.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/jh/6jhr ftp://data.pdbj.org/pub/pdb/validation_reports/jh/6jhr | HTTPS FTP |
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-Related structure data
Related structure data | 9828MC 9827C 9829C 9830C 6jhqC 6jhsC 6jhtC M: map data used to model this data C: citing same article (ref.) |
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Similar structure data |
-Links
-Assembly
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Symmetry | Point symmetry: (Schoenflies symbol: I (icosahedral)) |
-Components
#1: Protein | 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 |
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#2: Protein | 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 | 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 | Mass: 23788.209 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Mus musculus (house mouse) |
#5: Antibody | Mass: 24208.324 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Mus musculus (house mouse) |
-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
-Sample preparation
Component |
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Source (natural) |
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Details of virus | Empty: NO / Enveloped: NO / Isolate: STRAIN / Type: VIRION | ||||||||||||||||||||||||
Buffer solution | pH: 7 | ||||||||||||||||||||||||
Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES | ||||||||||||||||||||||||
Vitrification | Cryogen name: ETHANE |
-Electron microscopy imaging
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
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Microscopy | Model: FEI TITAN KRIOS |
Electron gun | Electron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM |
Electron lens | Mode: BRIGHT FIELD |
Image recording | Electron dose: 1.3 e/Å2 / Film or detector model: GATAN K2 BASE (4k x 4k) |
-Processing
Software | Name: PHENIX / Version: 1.11.1_2575: / Classification: refinement | ||||||||||||||||||||||||
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EM software | Name: PHENIX / Category: 3D reconstruction | ||||||||||||||||||||||||
CTF correction | Type: NONE | ||||||||||||||||||||||||
3D reconstruction | Resolution: 3.68 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 7245 / Symmetry type: POINT | ||||||||||||||||||||||||
Refine LS restraints |
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