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Yorodumi- PDB-7uov: Native Lassa glycoprotein in complex with neutralizing antibodies... -
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-Basic information
Entry | Database: PDB / ID: 7uov | ||||||
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Title | Native Lassa glycoprotein in complex with neutralizing antibodies 12.1F and 37.2D | ||||||
Components |
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Keywords | VIRAL PROTEIN/IMMUNE SYSTEM / Lassa virus / Neutralizing antibody / N-linked glycans complex / VIRAL PROTEIN / VIRAL PROTEIN-IMMUNE SYSTEM complex | ||||||
Function / homology | Function and homology information host cell Golgi membrane / receptor-mediated endocytosis of virus by host cell / host cell endoplasmic reticulum membrane / fusion of virus membrane with host endosome membrane / viral envelope / virion attachment to host cell / host cell plasma membrane / virion membrane / membrane / metal ion binding Similarity search - Function | ||||||
Biological species | Homo sapiens (human) Lassa virus | ||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.75 Å | ||||||
Authors | Li, H. / Saphire, E.O. | ||||||
Funding support | United States, 1items
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Citation | Journal: Sci Transl Med / Year: 2022 Title: A cocktail of protective antibodies subverts the dense glycan shield of Lassa virus. Authors: Haoyang Li / Tierra Buck / Michelle Zandonatti / Jieyun Yin / Alex Moon-Walker / Jingru Fang / Anatoliy Koval / Megan L Heinrich / Megan M Rowland / Ruben Diaz Avalos / Sharon L Schendel / ...Authors: Haoyang Li / Tierra Buck / Michelle Zandonatti / Jieyun Yin / Alex Moon-Walker / Jingru Fang / Anatoliy Koval / Megan L Heinrich / Megan M Rowland / Ruben Diaz Avalos / Sharon L Schendel / Diptiben Parekh / Dawid Zyla / Adrian Enriquez / Stephanie Harkins / Brian Sullivan / Victoria Smith / Onyeka Chukwudozie / Reika Watanabe / James E Robinson / Robert F Garry / Luis M Branco / Kathryn M Hastie / Erica Ollmann Saphire / Abstract: Developing potent therapeutics and effective vaccines are the ultimate goals in controlling infectious diseases. Lassa virus (LASV), the causative pathogen of Lassa fever (LF), infects hundreds of ...Developing potent therapeutics and effective vaccines are the ultimate goals in controlling infectious diseases. Lassa virus (LASV), the causative pathogen of Lassa fever (LF), infects hundreds of thousands annually, but effective antivirals or vaccines against LASV infection are still lacking. Furthermore, neutralizing antibodies against LASV are rare. Here, we describe biochemical analyses and high-resolution cryo-electron microscopy structures of a therapeutic cocktail of three broadly protective antibodies that target the LASV glycoprotein complex (GPC), previously identified from survivors of multiple LASV infections. Structural and mechanistic analyses reveal compatible neutralizing epitopes and complementary neutralization mechanisms that offer high potency, broad range, and resistance to escape. These antibodies either circumvent or exploit specific glycans comprising the extensive glycan shield of GPC. Further, they require mammalian glycosylation, native GPC cleavage, and proper GPC trimerization. These findings guided engineering of a next-generation GPC antigen suitable for future neutralizing antibody and vaccine discovery. Together, these results explain protective mechanisms of rare, broad, and potent antibodies and identify a strategy for the rational design of therapeutic modalities against LF and related infectious diseases. | ||||||
History |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 7uov.cif.gz | 504 KB | Display | PDBx/mmCIF format |
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PDB format | pdb7uov.ent.gz | 406.1 KB | Display | PDB format |
PDBx/mmJSON format | 7uov.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 7uov_validation.pdf.gz | 3.3 MB | Display | wwPDB validaton report |
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Full document | 7uov_full_validation.pdf.gz | 3.3 MB | Display | |
Data in XML | 7uov_validation.xml.gz | 75.2 KB | Display | |
Data in CIF | 7uov_validation.cif.gz | 112 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/uo/7uov ftp://data.pdbj.org/pub/pdb/validation_reports/uo/7uov | HTTPS FTP |
-Related structure data
Related structure data | 26655MC 7uotC C: citing same article (ref.) M: map data used to model this data |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
-Assembly
Deposited unit |
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1 |
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-Components
-Glycoprotein ... , 2 types, 6 molecules ABCabc
#3: Protein | Mass: 29064.402 Da / Num. of mol.: 3 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Lassa virus / Strain: Mouse/Sierra Leone/Josiah/1976 / Gene: GPC, GP-C / Production host: Homo sapiens (human) / References: UniProt: P08669 #4: Protein | Mass: 26797.973 Da / Num. of mol.: 3 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Lassa virus / Strain: Mouse/Sierra Leone/Josiah/1976 / Gene: GPC, GP-C / Production host: Homo sapiens (human) / References: UniProt: P08669 |
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-Antibody , 4 types, 12 molecules HDFLEGTPRSOQ
#1: Antibody | Mass: 12731.153 Da / Num. of mol.: 3 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Production host: Drosophila melanogaster (fruit fly) #2: Antibody | Mass: 11602.884 Da / Num. of mol.: 3 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Production host: Drosophila melanogaster (fruit fly) #5: Antibody | Mass: 11412.506 Da / Num. of mol.: 3 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Production host: Drosophila melanogaster (fruit fly) #6: Antibody | Mass: 13946.536 Da / Num. of mol.: 3 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Production host: Drosophila melanogaster (fruit fly) |
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-Sugars , 7 types, 33 molecules
#7: Polysaccharide | beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta- ...beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose Source method: isolated from a genetically manipulated source #8: Polysaccharide | alpha-D-mannopyranose-(1-2)-alpha-D-mannopyranose-(1-3)-[alpha-D-mannopyranose-(1-6)]beta-D- ...alpha-D-mannopyranose-(1-2)-alpha-D-mannopyranose-(1-3)-[alpha-D-mannopyranose-(1-6)]beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose Source method: isolated from a genetically manipulated source #9: Polysaccharide | Source method: isolated from a genetically manipulated source #10: Polysaccharide | beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-[alpha-L-fucopyranose-(1- ...beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-[alpha-L-fucopyranose-(1-6)]2-acetamido-2-deoxy-beta-D-glucopyranose Source method: isolated from a genetically manipulated source #11: Polysaccharide | 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose Source method: isolated from a genetically manipulated source #12: Polysaccharide | Source method: isolated from a genetically manipulated source #13: Sugar | ChemComp-NAG / | |
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-Details
Has ligand of interest | N |
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-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 | Name: Native Lassa glycoprotein in complex with 12.1F-scFv and 37.2D-scFv Type: COMPLEX / Entity ID: #1-#6 / Source: MULTIPLE SOURCES |
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Buffer solution | pH: 7.5 |
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 / Nominal defocus max: 2000 nm / Nominal defocus min: 1000 nm |
Image recording | Electron dose: 50 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) |
-Processing
Software | Name: PHENIX / Version: 1.19.1_4122: / Classification: refinement | ||||||||||||||||||||||||
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CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||
3D reconstruction | Resolution: 2.75 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 286170 / Symmetry type: POINT | ||||||||||||||||||||||||
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