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- PDB-5fhc: Crystal Structure of Protective Human Antibodies 100 and 114 in C... -

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Basic information

Entry
Database: PDB / ID: 5fhc
TitleCrystal Structure of Protective Human Antibodies 100 and 114 in Complex with Ebola Virus Fusion Glycoprotein (GP)
Components
  • (Antibody 100 Fab ...) x 2
  • (Antibody 114 Fab ...) x 2
  • Envelope glycoprotein
  • Envelope glycoprotein,Envelope glycoprotein
KeywordsVIRAL PROTEIN/IMMUNE SYSTEM / Ig domain / Fab / immune system / fusion / ebola virus / glycoprotein / GP / VIRAL PROTEIN-IMMUNE SYSTEM complex
Function / homology
Function and homology information


host cell endoplasmic reticulum / viral budding from plasma membrane / clathrin-dependent endocytosis of virus by host cell / symbiont-mediated-mediated suppression of host tetherin activity / entry receptor-mediated virion attachment to host cell / host cell cytoplasm / symbiont-mediated suppression of host innate immune response / membrane raft / symbiont entry into host cell / fusion of virus membrane with host endosome membrane ...host cell endoplasmic reticulum / viral budding from plasma membrane / clathrin-dependent endocytosis of virus by host cell / symbiont-mediated-mediated suppression of host tetherin activity / entry receptor-mediated virion attachment to host cell / host cell cytoplasm / symbiont-mediated suppression of host innate immune response / membrane raft / symbiont entry into host cell / fusion of virus membrane with host endosome membrane / lipid binding / viral envelope / host cell plasma membrane / virion membrane / extracellular region / identical protein binding
Similarity search - Function
: / Filoviruses glycoprotein, extracellular domain / Filoviruses glycoprotein / Filovirus glycoprotein / Envelope glycoprotein GP2-like, HR1-HR2
Similarity search - Domain/homology
Envelope glycoprotein
Similarity search - Component
Biological speciesZaire ebolavirus
Homo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 6.704 Å
AuthorsGilman, M.S.A. / McLellan, J.S.
CitationJournal: Science / Year: 2016
Title: Structural and molecular basis for Ebola virus neutralization by protective human antibodies.
Authors: John Misasi / Morgan S A Gilman / Masaru Kanekiyo / Miao Gui / Alberto Cagigi / Sabue Mulangu / Davide Corti / Julie E Ledgerwood / Antonio Lanzavecchia / James Cunningham / Jean Jacques ...Authors: John Misasi / Morgan S A Gilman / Masaru Kanekiyo / Miao Gui / Alberto Cagigi / Sabue Mulangu / Davide Corti / Julie E Ledgerwood / Antonio Lanzavecchia / James Cunningham / Jean Jacques Muyembe-Tamfun / Ulrich Baxa / Barney S Graham / Ye Xiang / Nancy J Sullivan / Jason S McLellan /
Abstract: Ebola virus causes hemorrhagic fever with a high case fatality rate for which there is no approved therapy. Two human monoclonal antibodies, mAb100 and mAb114, in combination, protect nonhuman ...Ebola virus causes hemorrhagic fever with a high case fatality rate for which there is no approved therapy. Two human monoclonal antibodies, mAb100 and mAb114, in combination, protect nonhuman primates against all signs of Ebola virus disease, including viremia. Here, we demonstrate that mAb100 recognizes the base of the Ebola virus glycoprotein (GP) trimer, occludes access to the cathepsin-cleavage loop, and prevents the proteolytic cleavage of GP that is required for virus entry. We show that mAb114 interacts with the glycan cap and inner chalice of GP, remains associated after proteolytic removal of the glycan cap, and inhibits binding of cleaved GP to its receptor. These results define the basis of neutralization for two protective antibodies and may facilitate development of therapies and vaccines.
History
DepositionDec 21, 2015Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 16, 2016Provider: repository / Type: Initial release
Revision 1.1Mar 30, 2016Group: Database references
Revision 1.2Nov 13, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / citation / database_2 / pdbx_entry_details / pdbx_modification_feature / pdbx_struct_oper_list
Item: _citation.journal_id_CSD / _database_2.pdbx_DOI ..._citation.journal_id_CSD / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_oper_list.symmetry_operation

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
J: Envelope glycoprotein
K: Envelope glycoprotein,Envelope glycoprotein
A: Antibody 100 Fab heavy chain
B: Antibody 100 Fab light chain
L: Antibody 114 Fab light chain
H: Antibody 114 Fab heavy chain


Theoretical massNumber of molelcules
Total (without water)139,9206
Polymers139,9206
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)169.670, 169.670, 376.990
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number155
Space group name H-MH32

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Components

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Protein , 2 types, 2 molecules JK

#1: Protein Envelope glycoprotein / GP1 / 2 / GP


Mass: 10968.456 Da / Num. of mol.: 1 / Fragment: UNP residues 502-599
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Zaire ebolavirus (strain Mayinga-76) / Strain: Mayinga-76 / Gene: GP / Cell line (production host): HEK293 Cells / Production host: Homo sapiens (human) / References: UniProt: Q05320
#2: Protein Envelope glycoprotein,Envelope glycoprotein / GP1 / 2 / GP


Mass: 36316.125 Da / Num. of mol.: 1 / Fragment: UNP residues 1-302,UNP residues 1-302
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Zaire ebolavirus / Strain: Mayinga-76 / Gene: GP / Cell line (production host): HEK293 Cells / Production host: Homo sapiens (human) / References: UniProt: Q05320

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Antibody , 4 types, 4 molecules ABLH

#3: Antibody Antibody 100 Fab heavy chain


Mass: 24234.023 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Cell: PBMC / Cell line (production host): HEK293 Cells / Production host: Homo sapiens (human)
#4: Antibody Antibody 100 Fab light chain


Mass: 22255.602 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Cell: PBMC / Cell line (production host): HEK293 Cells / Production host: Homo sapiens (human)
#5: Antibody Antibody 114 Fab light chain


Mass: 22942.482 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Cell: PBMC / Cell line (production host): HEK293 Cells / Production host: Homo sapiens (human)
#6: Antibody Antibody 114 Fab heavy chain


Mass: 23203.109 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Cell: PBMC / Cell line (production host): HEK293 Cells / Production host: Homo sapiens (human)

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Details

Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 3.88 Å3/Da / Density % sol: 68.32 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 7.5
Details: Ternary complex of Ebola virus GP (mucin-like domain deleted) with 114 and 100 at 2.9mg/ml, 13.4% PEG 8000, 6.7% isopropanol, 0.2M ammonium sulfate, 0.1M HEPES pH 7.5, 0.01M GSH-GSSG (L- ...Details: Ternary complex of Ebola virus GP (mucin-like domain deleted) with 114 and 100 at 2.9mg/ml, 13.4% PEG 8000, 6.7% isopropanol, 0.2M ammonium sulfate, 0.1M HEPES pH 7.5, 0.01M GSH-GSSG (L-Glutathione reduced-L-Glutathione oxidized)

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 19-ID / Wavelength: 0.9792 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Oct 24, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9792 Å / Relative weight: 1
ReflectionResolution: 6.7→47.85 Å / Num. obs: 3952 / % possible obs: 99.7 % / Redundancy: 8.9 % / Biso Wilson estimate: 286.238 Å2 / CC1/2: 0.987 / Rmerge(I) obs: 0.301 / Rpim(I) all: 0.106 / Net I/σ(I): 8.9 / Num. measured all: 35041 / Scaling rejects: 12
Reflection shell

Diffraction-ID: 1 / Rejects: _

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. unique allCC1/2Rpim(I) all% possible all
6.7-7.499.41.6782.11035611040.3830.58100
14.99-47.857.80.07120.929383750.9970.02796.9

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
PHENIX1.9_1692refinement
MOSFLMdata reduction
Aimless0.5.2data scaling
PHASERphasing
PDB_EXTRACT3.15data extraction
Cootmodel building
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 6.704→47.848 Å / SU ML: 1.22 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 46.61 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.3434 202 5.11 %
Rwork0.2595 --
obs0.2648 3950 99.97 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 6.704→47.848 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8854 0 0 0 8854
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0079071
X-RAY DIFFRACTIONf_angle_d1.21912354
X-RAY DIFFRACTIONf_dihedral_angle_d13.293181
X-RAY DIFFRACTIONf_chiral_restr0.0461410
X-RAY DIFFRACTIONf_plane_restr0.0071587
LS refinement shellHighest resolution: 6.7039 Å
RfactorNum. reflection% reflection
Rfree0.3434 202 -
Rwork0.2595 3748 -
obs--100 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
13.30761.7205-0.13373.1134-1.430.4938-0.76960.25481.44280.8410.1773-0.38350.2501-1.3167-0.0013.14030.60460.30353.45880.32532.44848.291581.497729.7565
2-1.69881.4602-3.64040.84041.7544.96631.53870.509-0.2226-1.1051-1.98142.22791.7005-0.6466-0.05273.01670.35280.00123.478-0.13934.2957-36.103355.6767-43.6022
34.5047-0.5806-1.21242.80020.6854-3.06360.1392-1.2853-0.6407-1.44760.0401-0.46590.6466-1.5475-0.00014.5108-0.37890.26543.70310.14212.5414-23.619841.8723-45.5025
41.12133.4842.43432.1495-5.11442.7606-0.9060.90120.25881.58160.10081.4651-0.25370.5708-0.00042.9780.5016-0.0513.61740.41673.020925.792183.580322.8199
5-1.2282-3.47053.17662.11892.02262.5588-0.3480.0421-0.2355-0.93880.4989-0.25672.3871-0.4578-0.00123.453-0.5230.10113.03760.41892.737515.675877.1199-23.8363
64.8007-1.73033.910.7703-2.92151.51320.4332-0.06091.0501-0.9657-1.05440.74061.2943-0.17150.29413.126-0.28340.77782.49520.70083.45517.700881.7876-39.4208
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1(chain L)
2X-RAY DIFFRACTION2(chain A)
3X-RAY DIFFRACTION3(chain B)
4X-RAY DIFFRACTION4(chain H)
5X-RAY DIFFRACTION5(chain K)
6X-RAY DIFFRACTION6(chain J)

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