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- PDB-5vkm: Crystal structure of human CD22 Ig domains 1-3 in complex with al... -

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Basic information

Entry
Database: PDB / ID: 5vkm
TitleCrystal structure of human CD22 Ig domains 1-3 in complex with alpha 2-6 sialyllactose
ComponentsB-cell receptor CD22
KeywordsIMMUNE SYSTEM / Siglec / Sialic acid / carbohydrate binding protein
Function / homology
Function and homology information


IgM binding / regulation of B cell proliferation / negative regulation of B cell receptor signaling pathway / negative regulation of immunoglobulin production / negative regulation of calcium-mediated signaling / sialic acid binding / CD22 mediated BCR regulation / neuronal cell body membrane / CD4 receptor binding / B cell activation ...IgM binding / regulation of B cell proliferation / negative regulation of B cell receptor signaling pathway / negative regulation of immunoglobulin production / negative regulation of calcium-mediated signaling / sialic acid binding / CD22 mediated BCR regulation / neuronal cell body membrane / CD4 receptor binding / B cell activation / regulation of immune response / regulation of endocytosis / Antigen activates B Cell Receptor (BCR) leading to generation of second messengers / recycling endosome / Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell / carbohydrate binding / protein phosphatase binding / early endosome / cell adhesion / external side of plasma membrane / signaling receptor binding / cell surface / integral component of plasma membrane / extracellular exosome / integral component of membrane / plasma membrane / cytoplasm
Similarity search - Function
Immunoglobulin domain / CD80-like C2-set immunoglobulin domain / CD80-like, immunoglobulin C2-set / Immunoglobulin domain / Immunoglobulin subtype 2 / Immunoglobulin C-2 Type / Immunoglobulin / Immunoglobulin subtype / Ig-like domain profile. / Immunoglobulin-like domain ...Immunoglobulin domain / CD80-like C2-set immunoglobulin domain / CD80-like, immunoglobulin C2-set / Immunoglobulin domain / Immunoglobulin subtype 2 / Immunoglobulin C-2 Type / Immunoglobulin / Immunoglobulin subtype / Ig-like domain profile. / Immunoglobulin-like domain / Immunoglobulin-like domain superfamily / Immunoglobulin-like fold
Similarity search - Domain/homology
B-cell receptor CD22
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.2 Å
AuthorsJulien, J.P. / Ereno-Orbea, J. / Sicard, T.
Funding support Canada, 1items
OrganizationGrant numberCountry
CIHR, Banting 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 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 1.2Nov 20, 2019Group: Data collection / Database references / Category: chem_comp / pdbx_database_related / Item: _chem_comp.type / _pdbx_database_related.db_id
Revision 2.0Jul 29, 2020Group: Advisory / Atomic model ...Advisory / Atomic model / Data collection / Derived calculations / Structure summary
Category: atom_site / chem_comp ...atom_site / chem_comp / entity / pdbx_branch_scheme / pdbx_chem_comp_identifier / pdbx_entity_branch / pdbx_entity_branch_descriptor / pdbx_entity_branch_link / pdbx_entity_branch_list / pdbx_entity_nonpoly / pdbx_nonpoly_scheme / pdbx_struct_assembly_gen / pdbx_validate_close_contact / struct_asym / struct_conn / struct_site / struct_site_gen
Item: _atom_site.auth_asym_id / _atom_site.auth_seq_id ..._atom_site.auth_asym_id / _atom_site.auth_seq_id / _atom_site.label_asym_id / _atom_site.label_entity_id / _chem_comp.name / _chem_comp.type / _pdbx_struct_assembly_gen.asym_id_list / _pdbx_validate_close_contact.auth_asym_id_1 / _pdbx_validate_close_contact.auth_asym_id_2 / _pdbx_validate_close_contact.auth_seq_id_1 / _pdbx_validate_close_contact.auth_seq_id_2 / _struct_conn.pdbx_role / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id
Description: Carbohydrate remediation / Provider: repository / Type: Remediation

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: B-cell receptor CD22
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,1354
Polymers36,6601
Non-polymers1,4743
Water1,24369
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)124.283, 57.912, 48.081
Angle α, β, γ (deg.)90.00, 106.99, 90.00
Int Tables number5
Space group name H-MC121

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Components

#1: Protein B-cell receptor CD22 / B-lymphocyte cell adhesion molecule / BL-CAM / Sialic acid-binding Ig-like lectin 2 / Siglec-2 / T- ...B-lymphocyte cell adhesion molecule / BL-CAM / Sialic acid-binding Ig-like lectin 2 / Siglec-2 / T-cell surface antigen Leu-14


Mass: 36660.293 Da / Num. of mol.: 1 / Fragment: Extracellular domain residues 20-330 / Mutation: N67A,N112A,N135A,N164A,N231A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CD22, SIGLEC2 / Cell line (production host): HEK293 / Production host: Homo sapiens (human) / References: UniProt: P20273
#2: Polysaccharide alpha-D-mannopyranose-(1-3)-[alpha-D-mannopyranose-(1-6)]beta-D-mannopyranose-(1-4)-2-acetamido-2- ...alpha-D-mannopyranose-(1-3)-[alpha-D-mannopyranose-(1-6)]beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 910.823 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpa1-3[DManpa1-6]DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-Glycam Condensed SequenceGMML 1.0
WURCS=2.0/3,5,4/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5][a1122h-1a_1-5]/1-1-2-3-3/a4-b1_b4-c1_c3-d1_c6-e1WURCSPDB2Glycan 1.1.0
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{[(3+1)][a-D-Manp]{}[(6+1)][a-D-Manp]{}}}}}LINUCSPDB-CARE
#3: Polysaccharide N-acetyl-alpha-neuraminic acid-(2-6)-beta-D-galactopyranose


Type: oligosaccharide / Mass: 471.411 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DNeup5Aca2-6DGalpb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/2,2,1/[a2112h-1b_1-5][Aad21122h-2a_2-6_5*NCC/3=O]/1-2/a6-b2WURCSPDB2Glycan 1.1.0
[][b-D-Galp]{[(6+2)][a-D-Neup5Ac]{}}LINUCSPDB-CARE
#4: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 69 / 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: 2.26 Å3/Da / Density % sol: 45.5 %
Crystal growTemperature: 293 K / Method: vapor diffusion
Details: 30% PEG 4000, 0.2 M lithium chloride and 0.1 M Tris pH 8.5

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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: Oct 9, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97949 Å / Relative weight: 1
ReflectionResolution: 2.2→36.886 Å / Num. obs: 16865 / % possible obs: 99.6 % / Redundancy: 3.8 % / CC1/2: 0.995 / Rmerge(I) obs: 0.106 / Net I/σ(I): 9.9
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsCC1/2Rpim(I) all% possible allNum. unique obsRrim(I) all
2.2-2.283.80.54951.60.5970.333199.8
2.79-2.943.8030.1658.40.98399.711830.192

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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: 5VKJ

5vkj


Resolution: 2.2→36.886 Å / SU ML: 0.35 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 31.58 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.254 1669 10.01 %
Rwork0.2103 --
obs0.2147 16680 99.63 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.2→36.886 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2436 0 99 69 2604
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0032603
X-RAY DIFFRACTIONf_angle_d0.6083542
X-RAY DIFFRACTIONf_dihedral_angle_d10.5691557
X-RAY DIFFRACTIONf_chiral_restr0.042412
X-RAY DIFFRACTIONf_plane_restr0.004437
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.2-2.26470.37181370.33671229X-RAY DIFFRACTION100
2.2647-2.33780.39451390.33231256X-RAY DIFFRACTION100
2.3378-2.42140.37841390.31411248X-RAY DIFFRACTION100
2.4214-2.51830.36121380.28551238X-RAY DIFFRACTION100
2.5183-2.63290.31211380.26531240X-RAY DIFFRACTION100
2.6329-2.77160.32851390.24721249X-RAY DIFFRACTION100
2.7716-2.94520.30711370.26351236X-RAY DIFFRACTION100
2.9452-3.17250.31611390.24331250X-RAY DIFFRACTION100
3.1725-3.49150.26341400.2131257X-RAY DIFFRACTION100
3.4915-3.99630.21491400.19271263X-RAY DIFFRACTION100
3.9963-5.03280.19421390.15781256X-RAY DIFFRACTION99
5.0328-36.89150.19071440.15761289X-RAY DIFFRACTION99

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