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- PDB-7n6p: Crystal structure of the anti-EBOV and SUDV monoclonal antibody 1... -

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Basic information

Entry
Database: PDB / ID: 7n6p
TitleCrystal structure of the anti-EBOV and SUDV monoclonal antibody 1C3 Fab
Components
  • 1C3 Fab heavy chain
  • 1C3 Fab light chain
KeywordsIMMUNE SYSTEM / glycoprotein / antibody
Function / homologyImmunoglobulins / Immunoglobulin-like / Sandwich / Mainly Beta
Function and homology information
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / AB INITIO PHASING / Resolution: 2.15 Å
AuthorsMilligan, J.C. / Yu, X. / Buck, T. / Saphire, E.O.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)NIAID U19 AI142790 United States
CitationJournal: Cell / Year: 2022
Title: Asymmetric and non-stoichiometric glycoprotein recognition by two distinct antibodies results in broad protection against ebolaviruses.
Authors: Jacob C Milligan / Carl W Davis / Xiaoying Yu / Philipp A Ilinykh / Kai Huang / Peter J Halfmann / Robert W Cross / Viktoriya Borisevich / Krystle N Agans / Joan B Geisbert / Chakravarthy ...Authors: Jacob C Milligan / Carl W Davis / Xiaoying Yu / Philipp A Ilinykh / Kai Huang / Peter J Halfmann / Robert W Cross / Viktoriya Borisevich / Krystle N Agans / Joan B Geisbert / Chakravarthy Chennareddy / Arthur J Goff / Ashley E Piper / Sean Hui / Kelly C L Shaffer / Tierra Buck / Megan L Heinrich / Luis M Branco / Ian Crozier / Michael R Holbrook / Jens H Kuhn / Yoshihiro Kawaoka / Pamela J Glass / Alexander Bukreyev / Thomas W Geisbert / Gabriella Worwa / Rafi Ahmed / Erica Ollmann Saphire /
Abstract: Several ebolaviruses cause outbreaks of severe disease. Vaccines and monoclonal antibody cocktails are available to treat Ebola virus (EBOV) infections, but not Sudan virus (SUDV) or other ...Several ebolaviruses cause outbreaks of severe disease. Vaccines and monoclonal antibody cocktails are available to treat Ebola virus (EBOV) infections, but not Sudan virus (SUDV) or other ebolaviruses. Current cocktails contain antibodies that cross-react with the secreted soluble glycoprotein (sGP) that absorbs virus-neutralizing antibodies. By sorting memory B cells from EBOV infection survivors, we isolated two broadly reactive anti-GP monoclonal antibodies, 1C3 and 1C11, that potently neutralize, protect rodents from disease, and lack sGP cross-reactivity. Both antibodies recognize quaternary epitopes in trimeric ebolavirus GP. 1C11 bridges adjacent protomers via the fusion loop. 1C3 has a tripartite epitope in the center of the trimer apex. One 1C3 antigen-binding fragment anchors simultaneously to the three receptor-binding sites in the GP trimer, and separate 1C3 paratope regions interact differently with identical residues on the three protomers. A cocktail of both antibodies completely protected nonhuman primates from EBOV and SUDV infections, indicating their potential clinical value.
History
DepositionJun 8, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 6, 2022Provider: repository / Type: Initial release
Revision 1.1Nov 6, 2024Group: Data collection / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / pdbx_entry_details / pdbx_modification_feature

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
H: 1C3 Fab heavy chain
L: 1C3 Fab light chain
A: 1C3 Fab heavy chain
B: 1C3 Fab light chain


Theoretical massNumber of molelcules
Total (without water)95,4274
Polymers95,4274
Non-polymers00
Water4,900272
1
H: 1C3 Fab heavy chain
L: 1C3 Fab light chain


Theoretical massNumber of molelcules
Total (without water)47,7132
Polymers47,7132
Non-polymers00
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3850 Å2
ΔGint-30 kcal/mol
Surface area18890 Å2
MethodPISA
2
A: 1C3 Fab heavy chain
B: 1C3 Fab light chain


Theoretical massNumber of molelcules
Total (without water)47,7132
Polymers47,7132
Non-polymers00
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3400 Å2
ΔGint-28 kcal/mol
Surface area18710 Å2
MethodPISA
Unit cell
Length a, b, c (Å)73.885, 83.737, 133.753
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

#1: Antibody 1C3 Fab heavy chain


Mass: 23876.879 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Cricetulus griseus (Chinese hamster)
#2: Antibody 1C3 Fab light chain


Mass: 23836.469 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Cricetulus griseus (Chinese hamster)
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 272 / Source method: isolated from a natural source / Formula: H2O
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: 2.17 Å3/Da / Density % sol: 43.34 %
Crystal growTemperature: 295 K / Method: vapor diffusion
Details: 100 mM CHES/Sodium hydroxide pH 9.5, 40% PEG 600 at 12 mg/ml

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL12-2 / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: May 18, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.15→83.74 Å / Num. obs: 45507 / % possible obs: 99.2 % / Redundancy: 8.3 % / CC1/2: 0.989 / Net I/σ(I): 8
Reflection shellResolution: 2.15→2.21 Å / Num. unique obs: 3452 / CC1/2: 0.579

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Processing

Software
NameVersionClassification
PHENIX(1.15rc1_3420)refinement
MOSFLMdata reduction
Aimlessdata scaling
PHENIXphasing
Cootmodel building
RefinementMethod to determine structure: AB INITIO PHASING / Resolution: 2.15→64.674 Å / SU ML: 0.23 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 22.08 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2309 1998 4.4 %
Rwork0.1752 --
obs0.1776 45427 99.04 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.15→64.674 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6608 0 0 272 6880
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0066769
X-RAY DIFFRACTIONf_angle_d0.7969214
X-RAY DIFFRACTIONf_dihedral_angle_d10.3653996
X-RAY DIFFRACTIONf_chiral_restr0.051046
X-RAY DIFFRACTIONf_plane_restr0.0051172
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.1501-2.20380.28921330.22972874X-RAY DIFFRACTION93
2.2038-2.26340.26931380.21972988X-RAY DIFFRACTION96
2.2634-2.330.28011380.21143022X-RAY DIFFRACTION98
2.33-2.40520.29121420.20393074X-RAY DIFFRACTION100
2.4052-2.49120.28011430.19363109X-RAY DIFFRACTION100
2.4912-2.59090.24531430.19053099X-RAY DIFFRACTION100
2.5909-2.70890.23391410.18883087X-RAY DIFFRACTION100
2.7089-2.85170.25771440.18393107X-RAY DIFFRACTION100
2.8517-3.03040.20441430.1753121X-RAY DIFFRACTION100
3.0304-3.26430.25221450.18083131X-RAY DIFFRACTION100
3.2643-3.59280.22141440.16253130X-RAY DIFFRACTION100
3.5928-4.11260.21571450.15863169X-RAY DIFFRACTION100
4.1126-5.18110.17681470.13773186X-RAY DIFFRACTION100
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)
12.68931.79012.04022.18513.58727.84540.0854-0.0171-0.14290.1340.06470.0210.363-0.0741-0.16280.2043-0.0279-0.01360.1001-0.00570.25358.5544-30.458-27.1346
25.8341-0.1803-0.92664.178-0.76834.55880.010.1114-0.16880.05510.0157-0.51390.03520.41-0.03750.13540.0042-0.04040.153-0.00660.234317.2759-29.4345-31.013
32.2479-1.3661-0.42445.1436-1.52845.44490.09250.16610.1638-0.11680.1207-0.20250.40720.1341-0.2570.1517-0.0255-0.00440.1266-0.03440.241214.958-24.3288-30.2018
44.3168-2.9722-0.58255.37770.62093.5626-0.2264-0.0845-0.50270.42730.01650.67530.5438-0.42610.1790.3549-0.070.05090.275-0.05670.25640.2945-13.5683-4.3619
52.2043-1.3325-0.78393.76651.65443.13380.02140.23510.0362-0.0755-0.0752-0.1193-0.0996-0.11990.02470.1097-0.00280.00560.15050.02310.130413.9401-6.2192-35.592
61.3549-0.2520.45353.3736-0.72236.9493-0.0125-0.1849-0.05690.57090.0122-0.0781-0.0231-0.1483-0.01260.27990.0414-0.0180.2225-0.04670.17159.0482-1.731.3904
72.71681.1089-0.14763.4124-3.43699.3214-0.2498-0.38560.5170.1297-0.0648-0.14540.1406-0.02420.13230.16920.0162-0.06040.2622-0.1440.452729.119237.3386-19.434
85.2523-3.02651.80276.1835-1.61527.28420.02950.0720.4771-0.2437-0.03640.18270.1726-0.101-0.07470.1973-0.0272-0.03720.2373-0.06170.428420.427435.7929-29.3758
95.0065-1.2294-0.28554.052-1.19516.8090.013-0.45130.61090.12190.0780.3838-0.2591-0.2779-0.24310.20680.0223-0.02330.258-0.1310.43922.935440.5115-21.9258
105.069-0.66332.9235.00170.74887.15140.27510.57340.1091-0.79770.01670.05470.05120.5632-0.30170.2963-0.0276-0.05040.2286-0.04520.356225.232331.4888-31.0903
113.8359-0.24551.26133.85530.02084.394-0.28260.2487-0.5876-0.16270.3709-0.4517-0.12710.5504-0.04590.3122-0.14520.12570.4224-0.19120.416740.327420.1344-6.0974
122.7326-1.23951.10215.0733-0.31593.38310.0540.21260.103-0.4149-0.14090.1116-0.03490.05010.07570.1582-0.0277-0.04620.1766-0.03240.247222.95514.8919-34.8943
132.6866-0.1171.30412.660.80768.54420.1138-0.3931-0.07590.4168-0.02440.01790.5448-0.1789-0.03310.3036-0.0478-0.00710.31770.00180.253933.61776.46050.661
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'H' and (resid 1 through 33 )
2X-RAY DIFFRACTION2chain 'H' and (resid 34 through 83 )
3X-RAY DIFFRACTION3chain 'H' and (resid 84 through 122 )
4X-RAY DIFFRACTION4chain 'H' and (resid 123 through 225 )
5X-RAY DIFFRACTION5chain 'L' and (resid 1 through 119 )
6X-RAY DIFFRACTION6chain 'L' and (resid 120 through 217 )
7X-RAY DIFFRACTION7chain 'A' and (resid 2 through 25 )
8X-RAY DIFFRACTION8chain 'A' and (resid 26 through 67 )
9X-RAY DIFFRACTION9chain 'A' and (resid 68 through 91 )
10X-RAY DIFFRACTION10chain 'A' and (resid 92 through 122 )
11X-RAY DIFFRACTION11chain 'A' and (resid 123 through 225 )
12X-RAY DIFFRACTION12chain 'B' and (resid 1 through 119 )
13X-RAY DIFFRACTION13chain 'B' and (resid 120 through 217 )

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