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- PDB-5chn: Fab fragments of chikungunya virus neutralizing human monoclonal ... -

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Basic information

Entry
Database: PDB / ID: 5chn
TitleFab fragments of chikungunya virus neutralizing human monoclonal antibody 5M16
Components
  • Antibody 5M16 Fab Heavy Chain
  • Antibody 5M16 Fab Light Chain
KeywordsIMMUNE SYSTEM / antibody
Function / homologyImmunoglobulins / Immunoglobulin-like / Sandwich / Mainly Beta
Function and homology information
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.047 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)R01 AI089591 United States
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)R01 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 10, 2015Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 11, 2015Provider: repository / Type: Initial release
Revision 1.1Nov 25, 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: Antibody 5M16 Fab Heavy Chain
L: Antibody 5M16 Fab Light Chain
A: Antibody 5M16 Fab Heavy Chain
B: Antibody 5M16 Fab Light Chain


Theoretical massNumber of molelcules
Total (without water)94,8504
Polymers94,8504
Non-polymers00
Water11,530640
1
H: Antibody 5M16 Fab Heavy Chain
L: Antibody 5M16 Fab Light Chain


Theoretical massNumber of molelcules
Total (without water)47,4252
Polymers47,4252
Non-polymers00
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3170 Å2
ΔGint-25 kcal/mol
Surface area19120 Å2
MethodPISA
2
A: Antibody 5M16 Fab Heavy Chain
B: Antibody 5M16 Fab Light Chain


Theoretical massNumber of molelcules
Total (without water)47,4252
Polymers47,4252
Non-polymers00
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3160 Å2
ΔGint-26 kcal/mol
Surface area19020 Å2
MethodPISA
Unit cell
Length a, b, c (Å)133.930, 133.930, 52.800
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number76
Space group name H-MP41

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Components

#1: Antibody Antibody 5M16 Fab Heavy Chain


Mass: 23400.182 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human)
#2: Antibody Antibody 5M16 Fab Light Chain


Mass: 24024.879 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human)
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 640 / 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: 2.5 Å3/Da / Density % sol: 51.07 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 8.5 / Details: PEG3350, Tris, ammonium formate

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 23-ID-B / Wavelength: 1.0332 Å
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Oct 11, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.0332 Å / Relative weight: 1
ReflectionResolution: 2.047→44.643 Å / Num. all: 402774 / Num. obs: 57761 / % possible obs: 97.2 % / Redundancy: 7 % / Rmerge(I) obs: 0.04 / Net I/σ(I): 28.4
Reflection shellResolution: 2.05→2.14 Å / Redundancy: 4.8 % / Rmerge(I) obs: 0.195 / Mean I/σ(I) obs: 6.9 / % possible all: 81

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Processing

Software
NameVersionClassification
PHENIX(1.10_2155: ???)refinement
PDB_EXTRACT3.15data extraction
XDSdata scaling
PHASERphasing
Cootmodel building
HKL-2000data reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3UJT and 4JY6

3ujt

4jy6


Resolution: 2.047→44.643 Å / SU ML: 0.21 / Cross valid method: FREE R-VALUE / σ(F): 1.38 / Phase error: 22.43 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2175 2861 4.95 %Random selection
Rwork0.1718 ---
obs0.1741 57741 97.07 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.047→44.643 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6514 0 0 640 7154
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0096675
X-RAY DIFFRACTIONf_angle_d1.0379115
X-RAY DIFFRACTIONf_dihedral_angle_d14.9892384
X-RAY DIFFRACTIONf_chiral_restr0.0611048
X-RAY DIFFRACTIONf_plane_restr0.0061165
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.047-2.08230.2787990.19812102X-RAY DIFFRACTION75
2.0823-2.12020.25821220.19032277X-RAY DIFFRACTION81
2.1202-2.16090.23311270.18792522X-RAY DIFFRACTION90
2.1609-2.2050.25281420.18622703X-RAY DIFFRACTION96
2.205-2.2530.26381530.19062765X-RAY DIFFRACTION100
2.253-2.30540.26551210.18922863X-RAY DIFFRACTION100
2.3054-2.3630.27471540.19142762X-RAY DIFFRACTION100
2.363-2.42690.2631400.18352833X-RAY DIFFRACTION100
2.4269-2.49830.2241740.18272770X-RAY DIFFRACTION100
2.4983-2.5790.25321600.18182801X-RAY DIFFRACTION100
2.579-2.67110.24051580.18122808X-RAY DIFFRACTION100
2.6711-2.77810.26161470.18252842X-RAY DIFFRACTION100
2.7781-2.90450.25071640.18332778X-RAY DIFFRACTION100
2.9045-3.05760.22891180.19352866X-RAY DIFFRACTION100
3.0576-3.24910.25071370.1922825X-RAY DIFFRACTION100
3.2491-3.49990.22041450.17482855X-RAY DIFFRACTION100
3.4999-3.85190.18621490.1672830X-RAY DIFFRACTION100
3.8519-4.40880.17241520.14112870X-RAY DIFFRACTION100
4.4088-5.5530.16331420.13152867X-RAY DIFFRACTION100
5.553-44.65390.18951570.17532941X-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)
10.0047-0.00830.01250.0144-0.01290.0086-0.05990.0262-0.0109-0.02310.0119-0.01510.010.08400.16310.0039-0.01050.23-0.02770.164140.5106-47.88644.7541
20.07440.0468-0.00730.0239-0.0140.1106-0.0661-0.0124-0.04380.02830.02670.04190.00630.0934-0.00730.18590.003-0.0060.1608-0.02880.142335.3768-50.19211.2536
30.0572-0.00730.02340.0623-0.03390.0419-0.05130.1270.1735-0.08950.0066-0.0744-0.0305-0.0189-0.00510.20850.0056-0.0110.15090.00430.290921.661-23.7714-6.1155
40.11760.0540.02720.11210.06080.05910.1168-0.07020.00130.0751-0.15640.0274-0.2084-0.1229-0.02160.2868-0.00040.01760.1587-0.01770.125833.7665-36.803526.7841
50.23510.2325-0.2680.3931-0.13490.5398-0.2318-0.12750.24080.33490.26090.1075-0.1608-0.29260.26830.29750.176-0.05450.194-0.0850.2359.8942-21.05075.3194
60.08020.010.06540.0505-0.02350.1863-0.06670.0415-0.0232-0.08990.0266-0.02810.0762-0.0071-0.15990.22550.01290.03250.14350.03530.1299-32.0705-64.305910.945
70.14490.03890.20020.05980.02450.29540.1044-0.14670.17540.06610.0033-0.2279-0.0198-0.07140.26780.1696-0.00880.08050.1710.00630.3447-8.0398-46.984626.6913
80.1351-0.0724-0.06350.0489-0.00270.21780.0688-0.01780.0911-0.25-0.0121-0.1040.00180.17760.16980.4852-0.08140.2260.14940.02960.0789-23.527-52.4686-6.6132
90.04460.05520.06030.3251-0.08030.1715-0.0190.0852-0.0764-0.33920.0841-0.49280.10770.22140.5370.096-0.02840.37110.19360.05920.56410.9911-51.236513.7316
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'H' and (resid 1 through 32 )
2X-RAY DIFFRACTION2chain 'H' and (resid 33 through 120 )
3X-RAY DIFFRACTION3chain 'H' and (resid 121 through 222 )
4X-RAY DIFFRACTION4chain 'L' and (resid 2 through 107 )
5X-RAY DIFFRACTION5chain 'L' and (resid 108 through 219 )
6X-RAY DIFFRACTION6chain 'A' and (resid 1 through 120 )
7X-RAY DIFFRACTION7chain 'A' and (resid 121 through 222 )
8X-RAY DIFFRACTION8chain 'B' and (resid 2 through 95 )
9X-RAY DIFFRACTION9chain 'B' and (resid 96 through 219 )

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