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- PDB-8dmh: Lymphocytic choriomeningitis virus glycoprotein in complex with n... -

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Basic information

Entry
Database: PDB / ID: 8dmh
TitleLymphocytic choriomeningitis virus glycoprotein in complex with neutralizing antibody M28
Components
  • (18.5C-M28 Fab ...) x 2
  • (Glycoprotein ...) x 2
KeywordsVIRAL PROTEIN/IMMUNE SYSTEM / Viral glycoprotein / arenavirus / LCMV / GP / antibody / neutralization / VIRAL PROTEIN / VIRAL PROTEIN-IMMUNE SYSTEM complex
Function / homology
Function and homology information


corrinoid adenosyltransferase activity / 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 / ATP binding ...corrinoid adenosyltransferase activity / 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 / ATP binding / membrane / metal ion binding
Similarity search - Function
Cobalamin adenosyltransferase-like / Corrinoid adenosyltransferase, PduO-type / Cobalamin adenosyltransferase / Cobalamin adenosyltransferase-like superfamily / Arenavirus glycoprotein, zinc binding domain / Arenavirus glycoprotein / Arenavirus glycoprotein
Similarity search - Domain/homology
Pre-glycoprotein polyprotein GP complex / Cobalamin adenosyltransferase-like domain-containing protein
Similarity search - Component
Biological speciesLymphocytic choriomeningitis virus
Homo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.19 Å
AuthorsMoon-Walker, A. / Hastie, K.M. / Zyla, D.S. / Saphire, E.O.
Funding support United States, Switzerland, 9items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)U19 AI 142790 United States
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)R01 A1132244 United States
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)R01AI14125 United States
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)R21AI137809 United States
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)F31-AI154700 United States
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)T32-AI125179 United States
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)P01 AI145815 United States
Swiss National Science FoundationP2EZP3_195680 Switzerland
Swiss National Science FoundationP500PB_210992 Switzerland
CitationJournal: Cell Chem Biol / Year: 2023
Title: Structural basis for antibody-mediated neutralization of lymphocytic choriomeningitis virus.
Authors: Alex Moon-Walker / Zeli Zhang / Dawid S Zyla / Tierra K Buck / Haoyang Li / Ruben Diaz Avalos / Sharon L Schendel / Kathryn M Hastie / Shane Crotty / Erica Ollmann Saphire /
Abstract: The mammarenavirus lymphocytic choriomeningitis virus (LCMV) is a globally distributed zoonotic pathogen that can be lethal in immunocompromised patients and can cause severe birth defects if ...The mammarenavirus lymphocytic choriomeningitis virus (LCMV) is a globally distributed zoonotic pathogen that can be lethal in immunocompromised patients and can cause severe birth defects if acquired during pregnancy. The structure of the trimeric surface glycoprotein, essential for entry, vaccine design, and antibody neutralization, remains unknown. Here, we present the cryoelectron microscopy (cryo-EM) structure of the LCMV surface glycoprotein (GP) in its trimeric pre-fusion assembly both alone and in complex with a rationally engineered monoclonal neutralizing antibody termed 18.5C-M28 (M28). Additionally, we show that passive administration of M28, either as a prophylactic or therapeutic, protects mice from LCMV clone 13 (LCMV) challenge. Our study illuminates not only the overall structural organization of LCMV GP and the mechanism for its inhibition by M28 but also presents a promising therapeutic candidate to prevent severe or fatal disease in individuals who are at risk of infection by a virus that poses a threat worldwide.
History
DepositionJul 8, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 12, 2023Provider: repository / Type: Initial release
Revision 1.1May 3, 2023Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Glycoprotein G1
E: 18.5C-M28 Fab Light Chain
F: 18.5C-M28 Fab Heavy Chain
a: Glycoprotein G2,Cobalamin adenosyltransferase-like domain-containing protein trimerization tag
B: Glycoprotein G1
G: 18.5C-M28 Fab Light Chain
H: 18.5C-M28 Fab Heavy Chain
b: Glycoprotein G2,Cobalamin adenosyltransferase-like domain-containing protein trimerization tag
C: Glycoprotein G1
I: 18.5C-M28 Fab Light Chain
J: 18.5C-M28 Fab Heavy Chain
c: Glycoprotein G2,Cobalamin adenosyltransferase-like domain-containing protein trimerization tag
hetero molecules


Theoretical massNumber of molelcules
Total (without water)353,26936
Polymers343,81612
Non-polymers9,45324
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, Assembly of the complex was confirmed by negative stain EM and cryoEM.
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Glycoprotein ... , 2 types, 6 molecules ABCabc

#1: Protein Glycoprotein G1


Mass: 25521.160 Da / Num. of mol.: 3 / Mutation: G207C, L264R, A265R
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Lymphocytic choriomeningitis virus / Strain: Clone 13 / Gene: GPC, GP-C, Segment S / Production host: Drosophila melanogaster (fruit fly) / References: UniProt: P09991
#4: Protein Glycoprotein G2,Cobalamin adenosyltransferase-like domain-containing protein trimerization tag / GP2


Mass: 42166.777 Da / Num. of mol.: 3 / Mutation: E334P,G366C,S398A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Lymphocytic choriomeningitis virus / Strain: Clone 13 / Gene: GPC, GP-C, Segment S, Ta1434 / Production host: Drosophila melanogaster (fruit fly) / References: UniProt: P09991, UniProt: Q9HIA7

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Antibody , 2 types, 6 molecules EGIFHJ

#2: Antibody 18.5C-M28 Fab Light Chain


Mass: 23306.834 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Cricetulus griseus (Chinese hamster)
#3: Antibody 18.5C-M28 Fab Heavy Chain


Mass: 23610.715 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Cricetulus griseus (Chinese hamster)

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Sugars , 3 types, 24 molecules

#5: 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


Type: oligosaccharide / Mass: 586.542 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/2,3,2/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5]/1-1-2/a4-b1_b4-c1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{}}}LINUCSPDB-CARE
#6: Polysaccharide
2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 424.401 Da / Num. of mol.: 15
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/1,2,1/[a2122h-1b_1-5_2*NCC/3=O]/1-1/a4-b1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}}LINUCSPDB-CARE
#7: Sugar
ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C8H15NO6
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0

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Details

Has ligand of interestN

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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
1Lymphocytic choriomeningitis virus glycoprotein in complex with neutralizing antibody M28COMPLEX#1-#40RECOMBINANT
2GlycoproteinCOMPLEX#1, #41RECOMBINANT
318.5C-M28 Fab Light Chain, 18.5C-M28 Fab Heavy ChainCOMPLEX#2-#31RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
12Lymphocytic choriomeningitis mammarenavirus11623
23Homo sapiens (human)9606
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
12Drosophila melanogaster (fruit fly)7227
23Cricetulus griseus (Chinese hamster)10029
Buffer solutionpH: 8
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 / Nominal defocus max: 2000 nm / Nominal defocus min: 1000 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.21rc1_4916 / Classification: refinement
EM softwareName: PHENIX / Version: 1.21rc1_4916 / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.19 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 34783 / Symmetry type: POINT
RefinementCross valid method: NONE
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
Displacement parametersBiso mean: 42.79 Å2
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.003214580
ELECTRON MICROSCOPYf_angle_d0.583919722
ELECTRON MICROSCOPYf_chiral_restr0.04472277
ELECTRON MICROSCOPYf_plane_restr0.00392421
ELECTRON MICROSCOPYf_dihedral_angle_d4.89661881

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