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- PDB-4nm4: Crystal structure of broadly neutralizing antibody CR8043 -

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Basic information

Entry
Database: PDB / ID: 4nm4
TitleCrystal structure of broadly neutralizing antibody CR8043
Components
  • Antibody CR8043, Heavy Chain
  • Antibody CR8043, Light Chain
KeywordsIMMUNE SYSTEM / Immune recognition / Antibody / Fab / Immunoglobulin / Influenza hemagglutinin
Function / homology
Function and homology information


IgD immunoglobulin complex / IgA immunoglobulin complex / IgM immunoglobulin complex / IgE immunoglobulin complex / CD22 mediated BCR regulation / IgG immunoglobulin complex / Fc epsilon receptor (FCERI) signaling / Classical antibody-mediated complement activation / Initial triggering of complement / immunoglobulin complex ...IgD immunoglobulin complex / IgA immunoglobulin complex / IgM immunoglobulin complex / IgE immunoglobulin complex / CD22 mediated BCR regulation / IgG immunoglobulin complex / Fc epsilon receptor (FCERI) signaling / Classical antibody-mediated complement activation / Initial triggering of complement / immunoglobulin complex / FCGR activation / immunoglobulin mediated immune response / Role of LAT2/NTAL/LAB on calcium mobilization / Role of phospholipids in phagocytosis / Scavenging of heme from plasma / antigen binding / FCERI mediated Ca+2 mobilization / FCGR3A-mediated IL10 synthesis / Antigen activates B Cell Receptor (BCR) leading to generation of second messengers / Regulation of Complement cascade / Cell surface interactions at the vascular wall / FCGR3A-mediated phagocytosis / FCERI mediated MAPK activation / B cell receptor signaling pathway / Regulation of actin dynamics for phagocytic cup formation / FCERI mediated NF-kB activation / Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell / blood microparticle / adaptive immune response / Potential therapeutics for SARS / immune response / extracellular space / extracellular exosome / extracellular region / plasma membrane
Similarity search - Function
: / : / : / Immunoglobulin V-Type / Immunoglobulin V-set domain / Immunoglobulin V-set domain / : / Immunoglobulin subtype / Immunoglobulin / Immunoglobulin/major histocompatibility complex, conserved site ...: / : / : / Immunoglobulin V-Type / Immunoglobulin V-set domain / Immunoglobulin V-set domain / : / Immunoglobulin subtype / Immunoglobulin / Immunoglobulin/major histocompatibility complex, conserved site / Immunoglobulins and major histocompatibility complex proteins signature. / Immunoglobulin C-Type / Immunoglobulin C1-set / Immunoglobulin C1-set domain / Ig-like domain profile. / Immunoglobulin-like domain / Immunoglobulin-like domain superfamily / Immunoglobulins / Immunoglobulin-like fold / Immunoglobulin-like / Sandwich / Mainly Beta
Similarity search - Domain/homology
DI(HYDROXYETHYL)ETHER / Immunoglobulin kappa constant / Immunoglobulin kappa light chain / Ig-like domain-containing protein / IgG H chain
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.65 Å
AuthorsLee, P.S. / Wilson, I.A.
CitationJournal: Proc Natl Acad Sci U S A / Year: 2014
Title: A common solution to group 2 influenza virus neutralization.
Authors: Robert H E Friesen / Peter S Lee / Esther J M Stoop / Ryan M B Hoffman / Damian C Ekiert / Gira Bhabha / Wenli Yu / Jarek Juraszek / Wouter Koudstaal / Mandy Jongeneelen / Hans J W M Korse / ...Authors: Robert H E Friesen / Peter S Lee / Esther J M Stoop / Ryan M B Hoffman / Damian C Ekiert / Gira Bhabha / Wenli Yu / Jarek Juraszek / Wouter Koudstaal / Mandy Jongeneelen / Hans J W M Korse / Carla Ophorst / Els C M Brinkman-van der Linden / Mark Throsby / Mark J Kwakkenbos / Arjen Q Bakker / Tim Beaumont / Hergen Spits / Ted Kwaks / Ronald Vogels / Andrew B Ward / Jaap Goudsmit / Ian A Wilson /
Abstract: The discovery and characterization of broadly neutralizing antibodies (bnAbs) against influenza viruses have raised hopes for the development of monoclonal antibody (mAb)-based immunotherapy and the ...The discovery and characterization of broadly neutralizing antibodies (bnAbs) against influenza viruses have raised hopes for the development of monoclonal antibody (mAb)-based immunotherapy and the design of universal influenza vaccines. Only one human bnAb (CR8020) specifically recognizing group 2 influenza A viruses has been previously characterized that binds to a highly conserved epitope at the base of the hemagglutinin (HA) stem and has neutralizing activity against H3, H7, and H10 viruses. Here, we report a second group 2 bnAb, CR8043, which was derived from a different germ-line gene encoding a highly divergent amino acid sequence. CR8043 has in vitro neutralizing activity against H3 and H10 viruses and protects mice against challenge with a lethal dose of H3N2 and H7N7 viruses. The crystal structure and EM reconstructions of the CR8043-H3 HA complex revealed that CR8043 binds to a site similar to the CR8020 epitope but uses an alternative angle of approach and a distinct set of interactions. The identification of another antibody against the group 2 stem epitope suggests that this conserved site of vulnerability has great potential for design of therapeutics and vaccines.
History
DepositionNov 14, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 25, 2013Provider: repository / Type: Initial release
Revision 1.1Jan 22, 2014Group: Database references
Revision 1.2Jun 21, 2017Group: Database references / Source and taxonomy / Structure summary
Category: entity_name_com / entity_src_nat ...entity_name_com / entity_src_nat / struct_ref / struct_ref_seq
Item: _struct_ref.db_code / _struct_ref.db_name ..._struct_ref.db_code / _struct_ref.db_name / _struct_ref.entity_id / _struct_ref.pdbx_align_begin / _struct_ref.pdbx_db_accession / _struct_ref.pdbx_seq_one_letter_code / _struct_ref_seq.db_align_beg / _struct_ref_seq.db_align_end / _struct_ref_seq.pdbx_auth_seq_align_beg / _struct_ref_seq.pdbx_auth_seq_align_end / _struct_ref_seq.pdbx_db_accession / _struct_ref_seq.pdbx_strand_id / _struct_ref_seq.ref_id / _struct_ref_seq.seq_align_beg / _struct_ref_seq.seq_align_end
Revision 1.3Sep 20, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
L: Antibody CR8043, Light Chain
H: Antibody CR8043, Heavy Chain
M: Antibody CR8043, Light Chain
I: Antibody CR8043, Heavy Chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)96,6267
Polymers96,3074
Non-polymers3183
Water1629
1
L: Antibody CR8043, Light Chain
H: Antibody CR8043, Heavy Chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)48,3664
Polymers48,1542
Non-polymers2122
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4270 Å2
ΔGint-16 kcal/mol
Surface area19730 Å2
MethodPISA
2
M: Antibody CR8043, Light Chain
I: Antibody CR8043, Heavy Chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)48,2603
Polymers48,1542
Non-polymers1061
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4320 Å2
ΔGint-19 kcal/mol
Surface area19690 Å2
MethodPISA
Unit cell
Length a, b, c (Å)59.954, 68.634, 72.401
Angle α, β, γ (deg.)78.67, 78.93, 86.18
Int Tables number1
Space group name H-MP1

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Components

#1: Antibody Antibody CR8043, Light Chain / Immunoglobulin kappa light chain EU


Mass: 24228.805 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: UniProt: P0DOX7, UniProt: P01834*PLUS
#2: Antibody Antibody CR8043, Heavy Chain


Mass: 23924.832 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: UniProt: Q6N089, UniProt: S6C4S0*PLUS
#3: Chemical ChemComp-PEG / DI(HYDROXYETHYL)ETHER


Mass: 106.120 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C4H10O3
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 9 / 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: 2.98 Å3/Da / Density % sol: 58.66 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 6.5
Details: 20% PEG 6000, 0.1 M HEPES pH 6.5, VAPOR DIFFUSION, SITTING DROP, temperature 277K

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Data collection

DiffractionMean temperature: 77 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL11-1 / Wavelength: 0.97945 Å
DetectorType: PSI PILATUS 6M / Detector: PIXEL / Date: Jun 24, 2011
RadiationMonochromator: Side scattering bent cube-root I-beam single crystal; asymmetric cut 4.965 degs
Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97945 Å / Relative weight: 1
ReflectionResolution: 2.65→50 Å / Num. all: 31483 / Num. obs: 31483 / % possible obs: 97.1 % / Observed criterion σ(I): -3 / Redundancy: 2.4 % / Biso Wilson estimate: 55 Å2 / Rmerge(I) obs: 0.086 / Rsym value: 0.086 / Net I/σ(I): 9
Reflection shellResolution: 2.65→2.77 Å / Redundancy: 2.3 % / Rmerge(I) obs: 0.515 / Mean I/σ(I) obs: 1.8 / Num. unique all: 4065 / Rsym value: 0.515 / % possible all: 93.8

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Processing

Software
NameVersionClassification
Blu-Icedata collection
PHASERphasing
PHENIX(phenix.refine: 1.8.1_1168)refinement
XDSdata reduction
XDSdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1VGE

1vge


Resolution: 2.65→44.447 Å / SU ML: 0.32 / σ(F): 1.99 / Phase error: 25.74 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2317 1577 5.02 %RANDOM
Rwork0.1751 ---
obs0.1781 31427 97.43 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.65→44.447 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6720 0 21 9 6750
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0096909
X-RAY DIFFRACTIONf_angle_d1.3589383
X-RAY DIFFRACTIONf_dihedral_angle_d16.2662452
X-RAY DIFFRACTIONf_chiral_restr0.0831049
X-RAY DIFFRACTIONf_plane_restr0.0071189
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.65-2.73550.36421270.27782710X-RAY DIFFRACTION96
2.7355-2.83330.28371370.24912703X-RAY DIFFRACTION97
2.8333-2.94670.3091360.22642725X-RAY DIFFRACTION98
2.9467-3.08080.28361430.21912691X-RAY DIFFRACTION98
3.0808-3.24320.2691520.20952741X-RAY DIFFRACTION98
3.2432-3.44630.23751430.19312730X-RAY DIFFRACTION98
3.4463-3.71220.24951560.17322704X-RAY DIFFRACTION98
3.7122-4.08560.20371380.16012736X-RAY DIFFRACTION98
4.0856-4.67620.20611780.13452679X-RAY DIFFRACTION98
4.6762-5.88940.18951230.13232758X-RAY DIFFRACTION98
5.8894-44.45310.18821440.1562673X-RAY DIFFRACTION96
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)
10.69320.08870.30443.16170.99922.55140.0497-0.2687-0.22920.4898-0.0144-0.22020.59080.0223-0.0170.51320.0262-0.04430.29650.05060.310115.0744-3.63618.8547
21.3466-0.4007-0.00021.78770.20221.55920.12490.1885-0.1368-0.0146-0.2332-0.09930.00850.12240.06510.53390.0256-0.10320.30660.09610.34779.5842-12.373-15.2798
31.72240.55680.46632.40710.431.9638-0.0326-0.06380.1494-0.3631-0.0860.3917-0.0798-0.10350.10990.31030.0301-0.05460.2060.00570.30298.526815.662310.3069
41.8357-0.28230.76862.4129-0.44471.8949-0.0530.0135-0.0731-0.4323-0.14530.6546-0.1014-0.33410.15160.50850.0423-0.1390.3574-0.08580.4457-5.414-5.9674-16.1323
53.4874-0.10960.54571.0050.07782.06150.07150.6461-0.3581-0.3273-0.0535-0.29130.11320.4686-0.01450.34640.03280.09480.4749-0.02960.366744.428829.18084.6673
62.7905-0.15250.08632.7255-0.37390.96190.1273-0.46-0.02070.4798-0.0676-0.1376-0.05170.1127-0.0430.3083-0.03320.08050.4947-0.07040.292254.12931.68140.8641
72.60870.4580.1872.41890.80222.0585-0.1421-0.11610.2781-0.1980.00040.1945-0.1616-0.08380.12640.26920.04350.0030.2490.01020.315226.170737.294314.1689
83.272-0.09330.74712.69830.40372.4984-0.2216-0.20570.5180.11430.0252-0.1842-0.6168-0.14190.15630.48130.00940.00260.3677-0.09350.388649.639146.771540.6838
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain H and resid 1:121
2X-RAY DIFFRACTION2chain H and resid 122:215
3X-RAY DIFFRACTION3chain L and resid 1:114
4X-RAY DIFFRACTION4chain L and resid 115:213
5X-RAY DIFFRACTION5chain I and resid 1:121
6X-RAY DIFFRACTION6chain I and resid 122:215
7X-RAY DIFFRACTION7chain M and resid 1:114
8X-RAY DIFFRACTION8chain M and resid 115:213

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