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- PDB-5d28: Complex of GM-CSF/IL-2 inhibition factor with Granulocyte-macroph... -

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Basic information

Entry
Database: PDB / ID: 5d28
TitleComplex of GM-CSF/IL-2 inhibition factor with Granulocyte-macrophage colony-stimulating factor
Components
  • GM-CSF/IL-2 inhibition factor
  • Granulocyte-macrophage colony-stimulating factor
KeywordsVIRAL PROTEIN / Signaling Protein / Cytokine / Host-pathogen interactions / Immunology
Function / homology
Function and homology information


granulocyte macrophage colony-stimulating factor receptor binding / neutrophil differentiation / positive regulation of interleukin-23 production / granulocyte macrophage colony-stimulating factor receptor complex / granulocyte-macrophage colony-stimulating factor signaling pathway / positive regulation of leukocyte proliferation / myeloid dendritic cell differentiation / cellular response to granulocyte macrophage colony-stimulating factor stimulus / positive regulation of macrophage derived foam cell differentiation / positive regulation of podosome assembly ...granulocyte macrophage colony-stimulating factor receptor binding / neutrophil differentiation / positive regulation of interleukin-23 production / granulocyte macrophage colony-stimulating factor receptor complex / granulocyte-macrophage colony-stimulating factor signaling pathway / positive regulation of leukocyte proliferation / myeloid dendritic cell differentiation / cellular response to granulocyte macrophage colony-stimulating factor stimulus / positive regulation of macrophage derived foam cell differentiation / positive regulation of podosome assembly / macrophage differentiation / monocyte differentiation / cell surface receptor signaling pathway via JAK-STAT / negative regulation of extrinsic apoptotic signaling pathway in absence of ligand / embryonic placenta development / cytokine activity / growth factor activity / cell population proliferation / immune response / negative regulation of DNA-templated transcription / intracellular membrane-bounded organelle / extracellular space
Similarity search - Function
Major secreted virus protein, 35kDa / Poxvirus chemokine inhibitor superfamily / Viral chemokine binding protein / Granulocyte-macrophage colony-stimulating factor / Granulocyte-macrophage colony-stimulating factor / Granulocyte-macrophage colony-stimulating factor signature. / Granulocyte-macrophage colony-simulating factor (GM-CSF) / Growth Hormone; Chain: A; - #10 / Four-helical cytokine-like, core / Growth Hormone; Chain: A; ...Major secreted virus protein, 35kDa / Poxvirus chemokine inhibitor superfamily / Viral chemokine binding protein / Granulocyte-macrophage colony-stimulating factor / Granulocyte-macrophage colony-stimulating factor / Granulocyte-macrophage colony-stimulating factor signature. / Granulocyte-macrophage colony-simulating factor (GM-CSF) / Growth Hormone; Chain: A; - #10 / Four-helical cytokine-like, core / Growth Hormone; Chain: A; / Up-down Bundle / Mainly Alpha
Similarity search - Domain/homology
Granulocyte-macrophage colony-stimulating factor / GM-CSF/IL-2 inhibition factor
Similarity search - Component
Biological speciesOrf virus
Ovis aries (sheep)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.845 Å
AuthorsFelix, J. / Savvides, S.N.
CitationJournal: Nat Commun / Year: 2016
Title: Structural basis of GM-CSF and IL-2 sequestration by the viral decoy receptor GIF.
Authors: Jan Felix / Eaazhisai Kandiah / Steven De Munck / Yehudi Bloch / Gydo C P van Zundert / Kris Pauwels / Ann Dansercoer / Katka Novanska / Randy J Read / Alexandre M J J Bonvin / Bjorn ...Authors: Jan Felix / Eaazhisai Kandiah / Steven De Munck / Yehudi Bloch / Gydo C P van Zundert / Kris Pauwels / Ann Dansercoer / Katka Novanska / Randy J Read / Alexandre M J J Bonvin / Bjorn Vergauwen / Kenneth Verstraete / Irina Gutsche / Savvas N Savvides /
Abstract: Subversion of the host immune system by viruses is often mediated by molecular decoys that sequester host proteins pivotal to mounting effective immune responses. The widespread mammalian pathogen ...Subversion of the host immune system by viruses is often mediated by molecular decoys that sequester host proteins pivotal to mounting effective immune responses. The widespread mammalian pathogen parapox Orf virus deploys GIF, a member of the poxvirus immune evasion superfamily, to antagonize GM-CSF (granulocyte macrophage colony-stimulating factor) and IL-2 (interleukin-2), two pleiotropic cytokines of the mammalian immune system. However, structural and mechanistic insights into the unprecedented functional duality of GIF have remained elusive. Here we reveal that GIF employs a dimeric binding platform that sequesters two copies of its target cytokines with high affinity and slow dissociation kinetics to yield distinct complexes featuring mutually exclusive interaction footprints. We illustrate how GIF serves as a competitive decoy receptor by leveraging binding hotspots underlying the cognate receptor interactions of GM-CSF and IL-2, without sharing any structural similarity with the cytokine receptors. Our findings contribute to the tracing of novel molecular mimicry mechanisms employed by pathogenic viruses.
History
DepositionAug 5, 2015Deposition site: RCSB / Processing site: PDBE
Revision 1.0Nov 16, 2016Provider: repository / Type: Initial release
Revision 1.1Mar 7, 2018Group: Data collection / Category: diffrn_source / Item: _diffrn_source.pdbx_synchrotron_site
Revision 1.2Apr 3, 2019Group: Data collection / Source and taxonomy / Category: entity_src_gen / Item: _entity_src_gen.pdbx_host_org_cell_line
Revision 2.0Jul 29, 2020Group: Advisory / Atomic model ...Advisory / Atomic model / Data collection / Derived calculations / Source and taxonomy / Structure summary
Category: atom_site / atom_site_anisotrop ...atom_site / atom_site_anisotrop / chem_comp / database_PDB_caveat / entity / entity_src_gen / 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_chiral / struct_asym / struct_conn / struct_site / struct_site_gen
Item: _atom_site.B_iso_or_equiv / _atom_site.Cartn_x ..._atom_site.B_iso_or_equiv / _atom_site.Cartn_x / _atom_site.Cartn_y / _atom_site.Cartn_z / _atom_site.auth_asym_id / _atom_site.auth_atom_id / _atom_site.auth_comp_id / _atom_site.auth_seq_id / _atom_site.label_asym_id / _atom_site.label_atom_id / _atom_site.label_comp_id / _atom_site.label_entity_id / _atom_site.type_symbol / _atom_site_anisotrop.U[1][1] / _atom_site_anisotrop.U[1][2] / _atom_site_anisotrop.U[1][3] / _atom_site_anisotrop.U[2][2] / _atom_site_anisotrop.U[2][3] / _atom_site_anisotrop.U[3][3] / _atom_site_anisotrop.pdbx_auth_asym_id / _atom_site_anisotrop.pdbx_auth_atom_id / _atom_site_anisotrop.pdbx_auth_comp_id / _atom_site_anisotrop.pdbx_auth_seq_id / _atom_site_anisotrop.pdbx_label_asym_id / _atom_site_anisotrop.pdbx_label_atom_id / _atom_site_anisotrop.pdbx_label_comp_id / _atom_site_anisotrop.type_symbol / _chem_comp.name / _chem_comp.type / _database_PDB_caveat.text / _entity.formula_weight / _entity.pdbx_description / _entity.pdbx_number_of_molecules / _entity.type / _pdbx_struct_assembly_gen.asym_id_list / _pdbx_validate_chiral.auth_asym_id / _pdbx_validate_chiral.auth_seq_id / _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
Revision 2.1Jan 10, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_conn
Item: _chem_comp.pdbx_synonyms / _database_2.pdbx_DOI ..._chem_comp.pdbx_synonyms / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_conn.pdbx_leaving_atom_flag
Revision 2.2Oct 16, 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
A: GM-CSF/IL-2 inhibition factor
B: Granulocyte-macrophage colony-stimulating factor
C: Granulocyte-macrophage colony-stimulating factor
D: GM-CSF/IL-2 inhibition factor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)87,80512
Polymers84,8244
Non-polymers2,9818
Water30617
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area8710 Å2
ΔGint5 kcal/mol
Surface area33620 Å2
MethodPISA
Unit cell
Length a, b, c (Å)145.700, 105.600, 73.490
Angle α, β, γ (deg.)90.00, 93.31, 90.00
Int Tables number5
Space group name H-MC121

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Components

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Protein , 2 types, 4 molecules ADBC

#1: Protein GM-CSF/IL-2 inhibition factor


Mass: 27985.777 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Orf virus / Gene: GIF / Cell line (production host): HEK293 T / Production host: Homo sapiens (human) / References: UniProt: Q9J5U5
#2: Protein Granulocyte-macrophage colony-stimulating factor / GM-CSF / Colony-stimulating factor / CSF


Mass: 14426.386 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Ovis aries (sheep) / Gene: CSF2 / Production host: Escherichia coli (E. coli) / References: UniProt: P28773

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Sugars , 3 types, 6 molecules

#3: Polysaccharide alpha-D-mannopyranose-(1-3)-beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1- ...alpha-D-mannopyranose-(1-3)-beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 748.682 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Orf virus / Cell line (production host): HEK293T / Production host: Homo sapiens (human)
DescriptorTypeProgram
DManpa1-3DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-Glycam Condensed SequenceGMML 1.0
WURCS=2.0/3,4,3/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5][a1122h-1a_1-5]/1-1-2-3/a4-b1_b4-c1_c3-d1WURCSPDB2Glycan 1.1.0
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{[(3+1)][b-D-Manp]{}}}}}LINUCSPDB-CARE
#4: Polysaccharide 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 424.401 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Orf virus / Cell line (production host): HEK293T / Production host: Homo sapiens (human)
DescriptorTypeProgram
DGlcpNAcb1-4DGlcpNAcb1-Glycam Condensed SequenceGMML 1.0
WURCS=2.0/1,2,1/[a2122h-1b_1-5_2*NCC/3=O]/1-1/a4-b1WURCSPDB2Glycan 1.1.0
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}}}LINUCSPDB-CARE
#5: Sugar ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Formula: C8H15NO6 / Source: (gene. exp.) Orf virus / Cell line (production host): HEK293T / Production host: Homo sapiens (human)
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0

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Non-polymers , 2 types, 19 molecules

#6: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO4
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 17 / Source method: isolated from a natural source / Formula: H2O

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Details

Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 3.28 Å3/Da / Density % sol: 62.45 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 6
Details: 0.15 M ammonium sulfate, 0.1 M MES pH 6.0, 24 % PEG 4000

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: PETRA III, EMBL c/o DESY / Beamline: P14 (MX2) / Wavelength: 0.976 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Oct 1, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.976 Å / Relative weight: 1
ReflectionResolution: 2.84→50 Å / Num. obs: 25798 / % possible obs: 98.2 % / Redundancy: 6.9 % / Rsym value: 0.073 / Net I/σ(I): 20.39
Reflection shellResolution: 2.84→2.96 Å / Redundancy: 6.7 % / Rmerge(I) obs: 1.12 / Mean I/σ(I) obs: 1.77 / % possible all: 95.7

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Processing

Software
NameVersionClassification
PHENIX1.9_1685refinement
XDSdata scaling
MOLREPphasing
XDSdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5D22, 2VGA, 1CQ3

5d22

2vga

1cq3


Resolution: 2.845→44.063 Å / SU ML: 0.35 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 26.51 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2353 1126 5.03 %
Rwork0.1905 --
obs0.1928 22384 85.46 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.845→44.063 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5487 0 102 17 5606
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0075743
X-RAY DIFFRACTIONf_angle_d0.947827
X-RAY DIFFRACTIONf_dihedral_angle_d11.8362081
X-RAY DIFFRACTIONf_chiral_restr0.04912
X-RAY DIFFRACTIONf_plane_restr0.006996
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.8447-2.97410.4036450.30311038X-RAY DIFFRACTION33
2.9741-3.13090.35861170.27372001X-RAY DIFFRACTION65
3.1309-3.3270.31981460.25242785X-RAY DIFFRACTION90
3.327-3.58370.26961610.21143063X-RAY DIFFRACTION99
3.5837-3.94420.23481660.18483051X-RAY DIFFRACTION99
3.9442-4.51440.20421620.15143087X-RAY DIFFRACTION99
4.5144-5.68580.18991670.1573108X-RAY DIFFRACTION99
5.6858-44.06830.21681620.19913125X-RAY DIFFRACTION99
Refinement TLS params.Method: refined / Origin x: 40.6418 Å / Origin y: -54.1475 Å / Origin z: -5.9087 Å
111213212223313233
T0.068 Å2-0.0165 Å2-0.0226 Å2-0.2034 Å2-0.0852 Å2--0.2893 Å2
L1.0327 °20.1365 °2-0.8689 °2-2.4339 °2-0.9845 °2--4.0278 °2
S0.1066 Å °-0.1362 Å °0.1219 Å °-0.2759 Å °-0.0421 Å °0.1836 Å °0.1425 Å °0.2793 Å °0.0285 Å °
Refinement TLS groupSelection details: all

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