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- PDB-6vyv: Human mAbs broadly protect against infection of arthritiogenic al... -

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Basic information

Entry
Database: PDB / ID: 6vyv
TitleHuman mAbs broadly protect against infection of arthritiogenic alphaviruses by recognizing conserved elements of the MXR8 receptor binding domain
Components
  • E1 glycoprotein
  • E2 glycoprotein
  • Fab CHK-265 heavy chain
  • Fab CHK-265 light chain
KeywordsVIRAL PROTEIN/IMMUNE SYSTEM / virus / monoclonal antibody / complex / VIRAL PROTEIN-IMMUNE SYSTEM complex
Function / homology
Function and homology information


togavirin / T=4 icosahedral viral capsid / symbiont-mediated suppression of host toll-like receptor signaling pathway / host cell cytoplasm / symbiont entry into host cell / serine-type endopeptidase activity / fusion of virus membrane with host endosome membrane / host cell nucleus / virion attachment to host cell / host cell plasma membrane ...togavirin / T=4 icosahedral viral capsid / symbiont-mediated suppression of host toll-like receptor signaling pathway / host cell cytoplasm / symbiont entry into host cell / serine-type endopeptidase activity / fusion of virus membrane with host endosome membrane / host cell nucleus / virion attachment to host cell / host cell plasma membrane / structural molecule activity / virion membrane / proteolysis / RNA binding / membrane
Similarity search - Function
Alphavirus E2 glycoprotein, domain B / Peptidase S3, togavirin / Alphavirus E2 glycoprotein / Alphavirus E3 spike glycoprotein / Alphavirus E1 glycoprotein / Alphavirus E2 glycoprotein, domain A / Alphavirus E2 glycoprotein, domain C / Alphavirus E2 glycoprotein / Alphavirus core protein / Alphavirus E3 glycoprotein ...Alphavirus E2 glycoprotein, domain B / Peptidase S3, togavirin / Alphavirus E2 glycoprotein / Alphavirus E3 spike glycoprotein / Alphavirus E1 glycoprotein / Alphavirus E2 glycoprotein, domain A / Alphavirus E2 glycoprotein, domain C / Alphavirus E2 glycoprotein / Alphavirus core protein / Alphavirus E3 glycoprotein / Alphavirus E1 glycoprotein / Alphavirus core protein (CP) domain profile. / Flavivirus/Alphavirus glycoprotein, immunoglobulin-like domain superfamily / Flavivirus glycoprotein, central and dimerisation domain superfamily / Flaviviral glycoprotein E, dimerisation domain / Immunoglobulin E-set / Peptidase S1, PA clan, chymotrypsin-like fold / Peptidase S1, PA clan
Similarity search - Domain/homology
Structural polyprotein
Similarity search - Component
Biological speciesRoss river virus
Homo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 6.33 Å
AuthorsMiller, A.S. / Kuhn, R.J.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)11000864 United States
CitationJournal: Cell Host Microbe / Year: 2020
Title: Human mAbs Broadly Protect against Arthritogenic Alphaviruses by Recognizing Conserved Elements of the Mxra8 Receptor-Binding Site.
Authors: Laura A Powell / Andrew Miller / Julie M Fox / Nurgun Kose / Thomas Klose / Arthur S Kim / Robin Bombardi / Rashika N Tennekoon / A Dharshan de Silva / Robert H Carnahan / Michael S Diamond ...Authors: Laura A Powell / Andrew Miller / Julie M Fox / Nurgun Kose / Thomas Klose / Arthur S Kim / Robin Bombardi / Rashika N Tennekoon / A Dharshan de Silva / Robert H Carnahan / Michael S Diamond / Michael G Rossmann / Richard J Kuhn / James E Crowe /
Abstract: Mosquito inoculation of humans with arthritogenic alphaviruses results in a febrile syndrome characterized by debilitating musculoskeletal pain and arthritis. Despite an expanding global disease ...Mosquito inoculation of humans with arthritogenic alphaviruses results in a febrile syndrome characterized by debilitating musculoskeletal pain and arthritis. Despite an expanding global disease burden, no approved therapies or licensed vaccines exist. Here, we describe human monoclonal antibodies (mAbs) that bind to and neutralize multiple distantly related alphaviruses. These mAbs compete for an antigenic site and prevent attachment to the recently discovered Mxra8 alphavirus receptor. Three cryoelectron microscopy structures of Fab in complex with Ross River (RRV), Mayaro, or chikungunya viruses reveal a conserved footprint of the broadly neutralizing mAb RRV-12 in a region of the E2 glycoprotein B domain. This mAb neutralizes virus in vitro by preventing virus entry and spread and is protective in vivo in mouse models. Thus, the RRV-12 mAb and its defined epitope have potential as a therapeutic agent or target of vaccine design against multiple emerging arthritogenic alphavirus infections.
History
DepositionFeb 27, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 26, 2020Provider: repository / Type: Initial release
Revision 1.1Nov 25, 2020Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.2Mar 6, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_struct_oper_list
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_oper_list.name / _pdbx_struct_oper_list.symmetry_operation / _pdbx_struct_oper_list.type

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Structure visualization

Movie
  • 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
  • EMDB-21473
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  • Superimposition on EM map
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Structure viewerMolecule:
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Assembly

Deposited unit
A: E1 glycoprotein
B: E1 glycoprotein
C: E1 glycoprotein
D: E1 glycoprotein
E: E2 glycoprotein
F: E2 glycoprotein
G: E2 glycoprotein
H: E2 glycoprotein
I: Fab CHK-265 heavy chain
M: Fab CHK-265 light chain
J: Fab CHK-265 heavy chain
N: Fab CHK-265 light chain
K: Fab CHK-265 heavy chain
O: Fab CHK-265 light chain
L: Fab CHK-265 heavy chain
P: Fab CHK-265 light chain


Theoretical massNumber of molelcules
Total (without water)510,36916
Polymers510,36916
Non-polymers00
Water00
1
A: E1 glycoprotein
B: E1 glycoprotein
C: E1 glycoprotein
D: E1 glycoprotein
E: E2 glycoprotein
F: E2 glycoprotein
G: E2 glycoprotein
H: E2 glycoprotein
I: Fab CHK-265 heavy chain
M: Fab CHK-265 light chain
J: Fab CHK-265 heavy chain
N: Fab CHK-265 light chain
K: Fab CHK-265 heavy chain
O: Fab CHK-265 light chain
L: Fab CHK-265 heavy chain
P: Fab CHK-265 light chain
x 60


Theoretical massNumber of molelcules
Total (without water)30,622,132960
Polymers30,622,132960
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: E1 glycoprotein
B: E1 glycoprotein
C: E1 glycoprotein
D: E1 glycoprotein
E: E2 glycoprotein
F: E2 glycoprotein
G: E2 glycoprotein
H: E2 glycoprotein
I: Fab CHK-265 heavy chain
M: Fab CHK-265 light chain
J: Fab CHK-265 heavy chain
N: Fab CHK-265 light chain
K: Fab CHK-265 heavy chain
O: Fab CHK-265 light chain
L: Fab CHK-265 heavy chain
P: Fab CHK-265 light chain
x 5


  • icosahedral pentamer
  • 2.55 MDa, 80 polymers
Theoretical massNumber of molelcules
Total (without water)2,551,84480
Polymers2,551,84480
Non-polymers00
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
point symmetry operation4
4
A: E1 glycoprotein
B: E1 glycoprotein
C: E1 glycoprotein
D: E1 glycoprotein
E: E2 glycoprotein
F: E2 glycoprotein
G: E2 glycoprotein
H: E2 glycoprotein
I: Fab CHK-265 heavy chain
M: Fab CHK-265 light chain
J: Fab CHK-265 heavy chain
N: Fab CHK-265 light chain
K: Fab CHK-265 heavy chain
O: Fab CHK-265 light chain
L: Fab CHK-265 heavy chain
P: Fab CHK-265 light chain
x 6


  • icosahedral 23 hexamer
  • 3.06 MDa, 96 polymers
Theoretical massNumber of molelcules
Total (without water)3,062,21396
Polymers3,062,21396
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
E1 glycoprotein


Mass: 42719.906 Da / Num. of mol.: 4 / Fragment: UNP residues 817-1209
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Ross river virus (strain T48) / Strain: T48 / Production host: Mesocricetus auratus (golden hamster) / References: UniProt: P08491, togavirin
#2: Protein
E2 glycoprotein


Mass: 38240.188 Da / Num. of mol.: 4 / Fragment: UNP residues 335-675
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Ross river virus (strain T48) / Strain: T48 / Production host: Mesocricetus auratus (golden hamster) / References: UniProt: P08491, togavirin
#3: Antibody
Fab CHK-265 heavy chain


Mass: 23743.719 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Cell line (production host): hybridoma / Production host: Homo sapiens (human)
#4: Antibody
Fab CHK-265 light chain


Mass: 22888.404 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Cell line (production host): hybridoma / Production host: Homo sapiens (human)

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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

ComponentName: Ross river virus (strain T48) / Type: VIRUS / Entity ID: #1-#2 / Source: RECOMBINANT
Source (natural)Organism: Ross river virus (strain T48)
Source (recombinant)Organism: Mesocricetus auratus (golden hamster) / Cell: BHK-21
Details of virusEmpty: NO / Enveloped: YES / Isolate: STRAIN / Type: VIRION
Buffer solutionpH: 7.5
SpecimenConc.: 3 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: COPPER / Grid type: C-flat
VitrificationInstrument: GATAN CRYOPLUNGE 3 / Cryogen name: ETHANE / Humidity: 85 %

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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 magnification: 18000 X / Cs: 2.7 mm / C2 aperture diameter: 100 µm
Specimen holderCryogen: NITROGEN
Image recordingElectron dose: 30 e/Å2 / Film or detector model: GATAN K2 BASE (4k x 4k)

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Processing

EM software
IDNameVersionCategory
1Appion2.2particle selection
2Leginonimage acquisition
4CTFFINDCTF correction
7EMfitmodel fitting
10jsprfinal Euler assignment
12jspr3D reconstruction
13PHENIXmodel refinement
CTF correctionType: PHASE FLIPPING ONLY
SymmetryPoint symmetry: I (icosahedral)
3D reconstructionResolution: 6.33 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 9559 / Symmetry type: POINT
Atomic model buildingProtocol: RIGID BODY FIT

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