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- PDB-5vkk: Crystal structure of Fab fragment of anti-CD22 Epratuzumab -

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Basic information

Entry
Database: PDB / ID: 5vkk
TitleCrystal structure of Fab fragment of anti-CD22 Epratuzumab
Components
  • Epratuzumab Fab Heavy Chain
  • Epratuzumab Fab Light Chain
KeywordsIMMUNE SYSTEM / therapeutic antibody / B cell
Function / homology
Function and homology information


immunoglobulin complex / adaptive immune response / extracellular region / metal ion binding / plasma membrane
Similarity search - Function
: / : / Immunoglobulin V-Type / Immunoglobulin V-set domain / Immunoglobulin V-set domain / Immunoglobulin/major histocompatibility complex, conserved site / Immunoglobulins and major histocompatibility complex proteins signature. / Immunoglobulin subtype / Immunoglobulin / Immunoglobulin C-Type ...: / : / Immunoglobulin V-Type / Immunoglobulin V-set domain / Immunoglobulin V-set domain / Immunoglobulin/major histocompatibility complex, conserved site / Immunoglobulins and major histocompatibility complex proteins signature. / Immunoglobulin subtype / Immunoglobulin / Immunoglobulin C-Type / Immunoglobulin C1-set / Immunoglobulin C1-set domain / Ig-like domain profile. / Immunoglobulin-like domain / Immunoglobulin-like domain superfamily / Immunoglobulin-like fold / Immunoglobulins / Immunoglobulin-like / Sandwich / Mainly Beta
Similarity search - Domain/homology
Ig-like domain-containing protein / Ig-like domain-containing protein
Similarity search - Component
Biological speciesMus musculus (house mouse)
Homo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.014 Å
AuthorsSicard, T. / Ereno-Orbea, J. / Julien, J.P.
Funding support Canada, 3items
OrganizationGrant numberCountry
Canadian Institutes of Health Research (CIHR)111111 Canada
Canadian Institutes of Health Research (CIHR)PJT-148811 Canada
Canadian Institutes of Health Research (CIHR)BPF-144483 Canada
CitationJournal: Nat Commun / Year: 2017
Title: Molecular basis of human CD22 function and therapeutic targeting.
Authors: June Ereño-Orbea / Taylor Sicard / Hong Cui / Mohammad T Mazhab-Jafari / Samir Benlekbir / Alba Guarné / John L Rubinstein / Jean-Philippe Julien /
Abstract: CD22 maintains a baseline level of B-cell inhibition to keep humoral immunity in check. As a B-cell-restricted antigen, CD22 is targeted in therapies against dysregulated B cells that cause ...CD22 maintains a baseline level of B-cell inhibition to keep humoral immunity in check. As a B-cell-restricted antigen, CD22 is targeted in therapies against dysregulated B cells that cause autoimmune diseases and blood cancers. Here we report the crystal structure of human CD22 at 2.1 Å resolution, which reveals that specificity for α2-6 sialic acid ligands is dictated by a pre-formed β-hairpin as a unique mode of recognition across sialic acid-binding immunoglobulin-type lectins. The CD22 ectodomain adopts an extended conformation that facilitates concomitant CD22 nanocluster formation on B cells and binding to trans ligands to avert autoimmunity in mammals. We structurally delineate the CD22 site targeted by the therapeutic antibody epratuzumab at 3.1 Å resolution and determine a critical role for CD22 N-linked glycosylation in antibody engagement. Our studies provide molecular insights into mechanisms governing B-cell inhibition and valuable clues for the design of immune modulators in B-cell dysfunction.The B-cell-specific co-receptor CD22 is a therapeutic target for depleting dysregulated B cells. Here the authors structurally characterize the ectodomain of CD22 and present its crystal structure with the bound therapeutic antibody epratuzumab, which gives insights into the mechanism of inhibition of B-cell activation.
History
DepositionApr 21, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 4, 2017Provider: repository / Type: Initial release
Revision 1.1Oct 11, 2017Group: Database references / Source and taxonomy
Category: entity_src_gen / struct_ref ...entity_src_gen / struct_ref / struct_ref_seq / struct_ref_seq_dif
Item: _entity_src_gen.gene_src_common_name / _entity_src_gen.pdbx_beg_seq_num ..._entity_src_gen.gene_src_common_name / _entity_src_gen.pdbx_beg_seq_num / _entity_src_gen.pdbx_end_seq_num / _entity_src_gen.pdbx_gene_src_gene / _entity_src_gen.pdbx_gene_src_ncbi_taxonomy_id / _entity_src_gen.pdbx_gene_src_scientific_name / _struct_ref.db_code / _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.seq_align_beg / _struct_ref_seq.seq_align_end
Revision 1.2Oct 25, 2017Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.name
Revision 1.3Jan 31, 2018Group: Structure summary / Category: audit_author / Item: _audit_author.name
Revision 1.4Jan 8, 2020Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.5Oct 4, 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
Revision 1.6Nov 13, 2024Group: Structure summary / Category: 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: Epratuzumab Fab Heavy Chain
L: Epratuzumab Fab Light Chain
A: Epratuzumab Fab Heavy Chain
B: Epratuzumab Fab Light Chain


Theoretical massNumber of molelcules
Total (without water)95,5904
Polymers95,5904
Non-polymers00
Water9,062503
1
H: Epratuzumab Fab Heavy Chain
L: Epratuzumab Fab Light Chain


Theoretical massNumber of molelcules
Total (without water)47,7952
Polymers47,7952
Non-polymers00
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3750 Å2
ΔGint-29 kcal/mol
Surface area19600 Å2
MethodPISA
2
A: Epratuzumab Fab Heavy Chain
B: Epratuzumab Fab Light Chain


Theoretical massNumber of molelcules
Total (without water)47,7952
Polymers47,7952
Non-polymers00
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3820 Å2
ΔGint-27 kcal/mol
Surface area19850 Å2
MethodPISA
Unit cell
Length a, b, c (Å)56.712, 61.564, 65.285
Angle α, β, γ (deg.)71.81, 81.07, 75.95
Int Tables number1
Space group name H-MP1

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Components

#1: Antibody Epratuzumab Fab Heavy Chain


Mass: 23741.412 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse), (gene. exp.) Homo sapiens (human)
Gene: DKFZp686P15220 / Production host: Homo sapiens (human) / References: UniProt: Q6N089
#2: Antibody Epratuzumab Fab Light Chain


Mass: 24053.707 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse), (gene. exp.) Homo sapiens (human)
Production host: Homo sapiens (human) / References: UniProt: Q8TCD0
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 503 / 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: 2.19 Å3/Da / Density % sol: 43.82 %
Crystal growTemperature: 293 K / Method: vapor diffusion
Details: 85 mM Tris, pH 8.5, 25.5% PEG 4000 (w/v), 170 mM sodium acetate and 15% glycerol

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: CLSI / Beamline: 08ID-1 / Wavelength: 0.97949 Å
DetectorType: RAYONIX MX-300 / Detector: CCD / Date: Aug 7, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97949 Å / Relative weight: 1
ReflectionResolution: 2.014→49.671 Å / Num. obs: 52026 / % possible obs: 92.3 % / Observed criterion σ(I): -3 / Redundancy: 2.957 % / CC1/2: 0.993 / Rmerge(I) obs: 0.145 / Rrim(I) all: 0.177 / Χ2: 0.963 / Net I/σ(I): 6.62
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. unique obsCC1/2Rrim(I) all% possible all
2.014-2.082.9790.7561.7151190.6260.92896
2.08-2.162.980.5982.1849350.670.73196.7
2.16-2.252.9880.5072.747740.7430.61996.9
2.25-2.352.9860.4243.2446280.8210.51696.8
2.35-2.462.9910.3493.9244000.860.42597
2.46-2.592.9910.2615.1341890.9140.31897.1
2.59-2.752.9840.1986.6739510.9480.2497.3
2.75-2.942.9820.1349.1637250.9750.16397.4
2.94-3.182.9920.09312.734430.9880.11297.2
3.18-3.482.9580.06516.6931930.9930.0896.9
3.48-3.892.9590.04820.9528700.9950.05996.8
3.89-4.492.9560.03825.125110.9960.04696.4
4.49-5.52.9260.03326.4621380.9970.0496.8
5.5-7.782.9220.03624.5516720.9970.04597.2
7.78-49.6712.9070.02830.199080.9980.03597.5

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Processing

Software
NameVersionClassification
PHENIX(1.12_2829)refinement
XSCALEdata scaling
PDB_EXTRACT3.22data extraction
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6ANI

6ani


Resolution: 2.014→49.671 Å / SU ML: 0.27 / Cross valid method: FREE R-VALUE / σ(F): 1.96 / Phase error: 26.3 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2366 2000 3.84 %
Rwork0.2121 --
obs0.2131 52020 96.98 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.014→49.671 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6681 0 0 503 7184
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0046853
X-RAY DIFFRACTIONf_angle_d0.8339329
X-RAY DIFFRACTIONf_dihedral_angle_d14.794095
X-RAY DIFFRACTIONf_chiral_restr0.0521044
X-RAY DIFFRACTIONf_plane_restr0.0051181
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.0144-2.06470.33381380.31773449X-RAY DIFFRACTION93
2.0647-2.12060.35911410.29693526X-RAY DIFFRACTION96
2.1206-2.1830.27081430.27683595X-RAY DIFFRACTION97
2.183-2.25340.25951430.26813563X-RAY DIFFRACTION97
2.2534-2.3340.3151440.2643591X-RAY DIFFRACTION97
2.334-2.42740.30421430.2553571X-RAY DIFFRACTION97
2.4274-2.53790.30861420.25193564X-RAY DIFFRACTION98
2.5379-2.67170.27791450.24553624X-RAY DIFFRACTION98
2.6717-2.83910.27571450.23223626X-RAY DIFFRACTION98
2.8391-3.05820.24941420.21493563X-RAY DIFFRACTION98
3.0582-3.36590.2241440.20073597X-RAY DIFFRACTION98
3.3659-3.85280.20271440.18173595X-RAY DIFFRACTION97
3.8528-4.85350.18041430.15683560X-RAY DIFFRACTION97
4.8535-49.68630.18121430.18453595X-RAY DIFFRACTION98
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)
11.5602-0.7757-0.38292.2738-0.82961.5394-0.0518-0.00750.5132-0.1622-0.0894-0.07140.02610.0357-0.06190.1801-0.04290.05640.24760.02290.180631.845852.380719.1016
21.3301-0.64010.52022.8059-0.1170.78250.00880.0579-0.0878-0.0437-0.04750.2730.02980.01270.04890.1884-0.05060.01630.24740.0130.249218.75253.726919.766
32.0754-1.31730.37014.0244-0.97421.0908-0.2658-0.6370.30210.33620.24860.2373-0.0758-0.40020.00110.23140.00350.04760.2655-0.05770.281319.316958.812329.2534
41.1433-0.3612-0.1512.05410.1790.8557-0.0689-0.08440.05920.22460.0483-0.00860.05780.16780.03050.2082-0.0188-0.00250.2318-0.02010.196128.184154.8123.4021
50.87140.6426-0.93661.78830.62281.54420.07460.20730.3425-0.3501-0.14650.3575-0.0645-0.19580.06910.1778-0.0113-0.02210.1540.03990.229717.699450.945413.6573
60.4038-0.5235-0.54391.5913-0.38860.70850.06240.0587-0.1576-0.1722-0.17450.37880.1050.02860.09140.15370.0132-0.04150.2005-0.02080.251341.344125.016715.8464
71.10240.80410.44881.40380.9072.0146-0.01280.1628-0.03-0.1775-0.10690.26290.09450.00550.07220.15410.0129-0.00980.2713-0.00490.190645.965426.56597.9684
81.20990.5262-0.19993.56430.31691.5932-0.0392-0.0624-0.2596-0.20580.0282-0.92560.15480.30560.11810.19450.06510.00480.28840.00270.256750.298622.55911.4371
91.65770.1232-0.66621.88930.5411.11750.0782-0.13810.22040.1097-0.04520.2761-0.0805-0.0710.0250.1986-0.05280.03770.2650.01230.28414.879839.804220.3204
101.1296-0.28340.26360.68750.00780.43020.00940.06560.0449-0.0528-0.0280.1122-0.0033-0.02640.0290.1896-0.05220.04880.24420.01880.199917.726232.502416.2571
112.966-0.00590.70881.59660.46590.9234-0.1691-0.11990.01390.07990.1682-0.04990.0401-0.04590.01010.23020.00420.01320.21060.01630.244830.970618.27923.4568
122.2569-0.24640.67130.72450.32860.51080.0051-0.2651-0.37960.40360.1943-0.16990.2639-0.0515-0.20120.3010.0321-0.07290.33020.07740.368241.279710.779228.4954
133.21140.2029-0.71022.8458-0.11242.74350.1542-0.1076-0.18030.0269-0.22060.34340.32210.134-0.08650.26460.0095-0.04210.18630.01210.1872.950117.423343.9654
142.0665-0.26560.23252.67740.41382.00330.1055-0.09010.00270.0840.0575-0.0498-0.0988-0.1523-0.16920.28320.0562-0.05230.2876-0.0230.18236.438629.917748.2776
151.11710.32740.78822.2090.11971.10890.0508-0.0452-0.02370.03510.020.12740.0245-0.1323-0.01770.23520.0467-0.01360.2-0.00680.17793.671227.683244.7202
160.6919-0.4194-0.24551.78120.70390.20370.21130.1653-0.0708-0.2188-0.36890.26450.17220.18320.17140.36690.1194-0.06260.3147-0.02410.251323.3391-2.547548.1397
171.83760.17890.67732.33371.44291.9056-0.0073-0.28180.0364-0.0942-0.31110.5718-0.0396-0.44810.14730.35860.00510.01670.3964-0.05720.320920.757-2.772454.1944
180.7149-0.28180.21491.62190.32770.7350.02090.10490.0819-0.29210.0417-0.1864-0.21810.1147-0.04440.3388-0.0408-0.01430.2224-0.00630.262822.445931.75357.9131
191.0604-1.43930.31852.24731.76451.65930.37320.23140.3377-0.548-0.0023-0.7974-0.22260.2264-0.20330.45580.06830.12910.3393-0.02740.44736.2976-1.172148.0174
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'H' and (resid 2 through 23 )
2X-RAY DIFFRACTION2chain 'H' and (resid 24 through 52 )
3X-RAY DIFFRACTION3chain 'H' and (resid 53 through 67 )
4X-RAY DIFFRACTION4chain 'H' and (resid 68 through 91 )
5X-RAY DIFFRACTION5chain 'H' and (resid 92 through 109 )
6X-RAY DIFFRACTION6chain 'H' and (resid 110 through 191 )
7X-RAY DIFFRACTION7chain 'H' and (resid 192 through 203 )
8X-RAY DIFFRACTION8chain 'H' and (resid 204 through 219 )
9X-RAY DIFFRACTION9chain 'L' and (resid 1 through 38 )
10X-RAY DIFFRACTION10chain 'L' and (resid 39 through 133 )
11X-RAY DIFFRACTION11chain 'L' and (resid 134 through 179 )
12X-RAY DIFFRACTION12chain 'L' and (resid 180 through 219 )
13X-RAY DIFFRACTION13chain 'A' and (resid 3 through 24 )
14X-RAY DIFFRACTION14chain 'A' and (resid 25 through 51 )
15X-RAY DIFFRACTION15chain 'A' and (resid 52 through 109 )
16X-RAY DIFFRACTION16chain 'A' and (resid 110 through 148 )
17X-RAY DIFFRACTION17chain 'A' and (resid 149 through 219 )
18X-RAY DIFFRACTION18chain 'B' and (resid 1 through 118 )
19X-RAY DIFFRACTION19chain 'B' and (resid 119 through 219 )

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