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- PDB-5cgy: Fab fragment of Chikungunya virus neutralizing human monoclonal a... -

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Basic information

Entry
Database: PDB / ID: 5cgy
TitleFab fragment of Chikungunya virus neutralizing human monoclonal antibody 4J21
Components
  • Heavy Chain of Fab
  • Light Chain of Fab
KeywordsIMMUNE SYSTEM / antibody / Fab
Function / homologyImmunoglobulins / Immunoglobulin-like / Sandwich / Mainly Beta
Function and homology information
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.07 Å
AuthorsLong, F. / Crowe, J.E. / Rossmann, M.G.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)RO1 AI095366 United States
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)RO1 AI114816 United States
CitationJournal: Proc Natl Acad Sci U S A / Year: 2015
Title: Cryo-EM structures elucidate neutralizing mechanisms of anti-chikungunya human monoclonal antibodies with therapeutic activity.
Authors: Feng Long / Rachel H Fong / Stephen K Austin / Zhenguo Chen / Thomas Klose / Andrei Fokine / Yue Liu / Jason Porta / Gopal Sapparapu / Wataru Akahata / Benjamin J Doranz / James E Crowe / ...Authors: Feng Long / Rachel H Fong / Stephen K Austin / Zhenguo Chen / Thomas Klose / Andrei Fokine / Yue Liu / Jason Porta / Gopal Sapparapu / Wataru Akahata / Benjamin J Doranz / James E Crowe / Michael S Diamond / Michael G Rossmann /
Abstract: Chikungunya virus (CHIKV) is a mosquito-transmitted alphavirus that causes severe acute and chronic disease in humans. Although highly inhibitory murine and human monoclonal antibodies (mAbs) have ...Chikungunya virus (CHIKV) is a mosquito-transmitted alphavirus that causes severe acute and chronic disease in humans. Although highly inhibitory murine and human monoclonal antibodies (mAbs) have been generated, the structural basis of their neutralizing activity remains poorly characterized. Here, we determined the cryo-EM structures of chikungunya virus-like particles complexed with antibody fragments (Fab) of two highly protective human mAbs, 4J21 and 5M16, that block virus fusion with host membranes. Both mAbs bind primarily to sites within the A and B domains, as well as to the B domain's β-ribbon connector of the viral glycoprotein E2. The footprints of these antibodies on the viral surface were consistent with results from loss-of-binding studies using an alanine scanning mutagenesis-based epitope mapping approach. The Fab fragments stabilized the position of the B domain relative to the virus, particularly for the complex with 5M16. This finding is consistent with a mechanism of neutralization in which anti-CHIKV mAbs that bridge the A and B domains impede movement of the B domain away from the underlying fusion loop on the E1 glycoprotein and therefore block the requisite pH-dependent fusion of viral and host membranes.
History
DepositionJul 9, 2015Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 11, 2015Provider: repository / Type: Initial release
Revision 1.1Nov 18, 2015Group: Database references
Revision 1.2Sep 20, 2017Group: Author supporting evidence / Database references / Derived calculations
Category: citation / pdbx_audit_support / pdbx_struct_oper_list
Item: _citation.journal_id_CSD / _pdbx_audit_support.funding_organization / _pdbx_struct_oper_list.symmetry_operation
Revision 1.3Dec 11, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.4Sep 27, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
H: Heavy Chain of Fab
L: Light Chain of Fab
C: Heavy Chain of Fab
D: Light Chain of Fab


Theoretical massNumber of molelcules
Total (without water)93,6104
Polymers93,6104
Non-polymers00
Water13,187732
1
H: Heavy Chain of Fab
L: Light Chain of Fab


Theoretical massNumber of molelcules
Total (without water)46,8052
Polymers46,8052
Non-polymers00
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3270 Å2
ΔGint-25 kcal/mol
Surface area19200 Å2
MethodPISA
2
C: Heavy Chain of Fab
D: Light Chain of Fab


Theoretical massNumber of molelcules
Total (without water)46,8052
Polymers46,8052
Non-polymers00
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3180 Å2
ΔGint-25 kcal/mol
Surface area19200 Å2
MethodPISA
Unit cell
Length a, b, c (Å)39.224, 127.588, 83.912
Angle α, β, γ (deg.)90.000, 97.700, 90.000
Int Tables number4
Space group name H-MP1211

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Components

#1: Antibody Heavy Chain of Fab


Mass: 24403.186 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human)
#2: Antibody Light Chain of Fab


Mass: 22401.799 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human)
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 732 / Source method: isolated from a natural source / Formula: H2O

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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: 2.23 Å3/Da / Density % sol: 44.95 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 8.5 / Details: PEG2000, Tris, ammonium acetate

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 14-BM-C / Wavelength: 0.9787 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Aug 22, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9787 Å / Relative weight: 1
ReflectionResolution: 2.07→40 Å / Num. obs: 55062 / % possible obs: 94.2 % / Redundancy: 4.1 % / Rsym value: 0.08 / Net I/σ(I): 21.7
Reflection shellResolution: 2.07→2.15 Å / Redundancy: 4.2 % / Rmerge(I) obs: 0.28 / Mean I/σ(I) obs: 6.2 / % possible all: 98.5

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Processing

Software
NameVersionClassification
PHENIX1.9_1692refinement
PDB_EXTRACT3.15data extraction
HKL-2000data scaling
PHASERphasing
HKL-2000data reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3UJT, 4JY6

3ujt

4jy6


Resolution: 2.07→33.194 Å / SU ML: 0.21 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 24.04 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2162 1919 3.9 %Random selection
Rwork0.1675 47232 --
obs0.1694 49151 98.89 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 91.06 Å2 / Biso mean: 30.9283 Å2 / Biso min: 8.85 Å2
Refinement stepCycle: final / Resolution: 2.07→33.194 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6505 0 0 732 7237
Biso mean---37.96 -
Num. residues----869
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0086687
X-RAY DIFFRACTIONf_angle_d1.1899151
X-RAY DIFFRACTIONf_chiral_restr0.0551029
X-RAY DIFFRACTIONf_plane_restr0.0051165
X-RAY DIFFRACTIONf_dihedral_angle_d22.1553643
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 14

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.07-2.12180.26851010.20313333343498
2.1218-2.17910.25532020.1943345354799
2.1791-2.24330.22541010.17573346344798
2.2433-2.31560.24841010.18293445354699
2.3156-2.39840.2512020.18633251345399
2.3984-2.49440.28161010.193424352599
2.4944-2.60790.24941010.18453422352399
2.6079-2.74530.23332020.18563278348099
2.7453-2.91720.26541010.1773423352499
2.9172-3.14230.23492020.17563347354999
3.1423-3.45820.19981010.16893421352299
3.4582-3.95790.22891010.1523455355699
3.9579-4.98380.1512020.13043329353199
4.9838-33.19790.20571010.16333413351497
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)
10.0381-0.0196-0.01520.07860.01070.0951-0.0094-0.001-0.0081-0.09510.033-0.05230.0910.07970.01280.1153-0.0163-0.00540.1125-0.01280.1158.861916.7682-23.8923
20.43020.0098-0.01920.0319-0.01240.01440.09880.1395-0.14290.2454-0.0298-0.0757-0.0555-0.0481-0.00620.47240.0046-0.03110.15010.04430.14532.2156-16.3699-45.6484
30.02590.01120.00890.04630.00350.04940.0142-0.01650.0361-0.0337-0.0033-0.0466-0.1343-0.0281-0.00050.18430.0085-0.00120.1746-0.01360.09896.50123.8092-43.7176
40.0203-0.00810.00210.0425-0.01770.0234-0.0402-0.0722-0.06490.13680.14510.15360.0401-0.0170.04120.31220.00820.08760.13550.10660.2273-6.3361-2.554-49.397
50.2435-0.01710.12230.1656-0.01780.1917-0.0377-0.0151-0.0114-0.16190.1381-0.0933-0.21210.03050.10060.1783-0.02120.03370.1289-0.01450.123412.3842-35.6454-15.4256
60.27620.03660.1280.11540.04990.0825-0.055-0.22490.0204-0.32650.0695-0.11760.0484-0.17250.00230.4106-0.00960.0203-0.0193-0.04710.0948-3.4271-1.65612.9303
70.0659-0.0168-0.04890.0221-0.02770.0576-0.0053-0.0315-0.0285-0.07890.046-0.01780.0362-0.03250.03630.0708-0.0115-0.00020.1388-0.0030.11713.4939-41.70822.7303
80.2186-0.0614-0.08870.1760.04930.0648-0.1388-0.05430.0337-0.27840.1310.1083-0.05010.08030.03050.2745-0.0275-0.08550.06280.02510.1772-10.3816-16.95743.5396
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'H' and (resid 1 through 125)H0
2X-RAY DIFFRACTION2chain 'H' and (resid 126 through 228 )H0
3X-RAY DIFFRACTION3chain 'L' and (resid 2 through 105 )L0
4X-RAY DIFFRACTION4chain 'L' and (resid 106 through 213)L0
5X-RAY DIFFRACTION5chain 'C' and (resid 1 through 125 )C0
6X-RAY DIFFRACTION6chain 'C' and (resid 126 through 228 )C0
7X-RAY DIFFRACTION7chain 'D' and (resid 2 through 105)D0
8X-RAY DIFFRACTION8chain 'D' and (resid 106 through 213)D0

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