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- PDB-8ywq: Crystal structure of the Fab fragment of the anti-IL-6 antibody I... -

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Basic information

Entry
Database: PDB / ID: 8ywq
TitleCrystal structure of the Fab fragment of the anti-IL-6 antibody I9H in complex with a domain-swapped IL-6 dimer
Components
  • Heavy chain of the Fab fragment of anti-IL-6 antibody I9H
  • Interleukin-6
  • Light chain of the Fab fragment of anti-IL-6 antibody I9H
KeywordsIMMUNE SYSTEM / interleukin / dimer / swap
Function / homology
Function and homology information


regulation of astrocyte activation / glucagon secretion / positive regulation of interleukin-21 production / regulation of glucagon secretion / hepatic immune response / negative regulation of primary miRNA processing / regulation of vascular endothelial growth factor production / negative regulation of interleukin-1-mediated signaling pathway / regulation of microglial cell activation / interleukin-6 receptor complex ...regulation of astrocyte activation / glucagon secretion / positive regulation of interleukin-21 production / regulation of glucagon secretion / hepatic immune response / negative regulation of primary miRNA processing / regulation of vascular endothelial growth factor production / negative regulation of interleukin-1-mediated signaling pathway / regulation of microglial cell activation / interleukin-6 receptor complex / positive regulation of apoptotic DNA fragmentation / hepatocyte proliferation / positive regulation of type B pancreatic cell apoptotic process / neutrophil apoptotic process / germinal center B cell differentiation / positive regulation of extracellular matrix disassembly / response to peptidoglycan / interleukin-6 receptor binding / positive regulation of B cell activation / positive regulation of receptor signaling pathway via STAT / T-helper 17 cell lineage commitment / inflammatory response to wounding / positive regulation of T-helper 2 cell cytokine production / endocrine pancreas development / negative regulation of collagen biosynthetic process / regulation of neuroinflammatory response / positive regulation of acute inflammatory response / vascular endothelial growth factor production / negative regulation of chemokine production / T follicular helper cell differentiation / positive regulation of neuroinflammatory response / positive regulation of leukocyte chemotaxis / positive regulation of platelet aggregation / neutrophil mediated immunity / positive regulation of cytokine production involved in inflammatory response / cell surface receptor signaling pathway via STAT / positive regulation of leukocyte adhesion to vascular endothelial cell / negative regulation of bone resorption / CD163 mediating an anti-inflammatory response / positive regulation of peptidyl-tyrosine phosphorylation / positive regulation of immunoglobulin production / Interleukin-6 signaling / interleukin-6-mediated signaling pathway / negative regulation of fat cell differentiation / MAPK3 (ERK1) activation / maintenance of blood-brain barrier / MAPK1 (ERK2) activation / Interleukin-10 signaling / positive regulation of interleukin-17 production / monocyte chemotaxis / humoral immune response / Transcriptional Regulation by VENTX / positive regulation of interleukin-10 production / positive regulation of vascular endothelial growth factor production / positive regulation of glial cell proliferation / negative regulation of lipid storage / positive regulation of peptidyl-serine phosphorylation / regulation of angiogenesis / cell surface receptor signaling pathway via JAK-STAT / positive regulation of osteoblast differentiation / positive regulation of epithelial to mesenchymal transition / : / positive regulation of chemokine production / positive regulation of T cell proliferation / positive regulation of smooth muscle cell proliferation / liver regeneration / regulation of insulin secretion / response to glucocorticoid / positive regulation of translation / cytokine activity / positive regulation of interleukin-1 beta production / acute-phase response / response to activity / positive regulation of interleukin-8 production / positive regulation of receptor signaling pathway via JAK-STAT / Post-translational protein phosphorylation / growth factor activity / neuron cellular homeostasis / cellular response to virus / platelet activation / negative regulation of neurogenesis / positive regulation of interleukin-6 production / positive regulation of miRNA transcription / cellular response to hydrogen peroxide / Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) / cytokine-mediated signaling pathway / neuron projection development / positive regulation of tumor necrosis factor production / ADORA2B mediated anti-inflammatory cytokines production / glucose homeostasis / cellular response to lipopolysaccharide / Senescence-Associated Secretory Phenotype (SASP) / Interleukin-4 and Interleukin-13 signaling / defense response to Gram-negative bacterium / defense response to virus / positive regulation of MAPK cascade / defense response to Gram-positive bacterium / positive regulation of apoptotic process / endoplasmic reticulum lumen / inflammatory response
Similarity search - Function
Interleukin-6 / Interleukin-6/G-CSF/MGF family / Interleukin-6/GCSF/MGF, conserved site / Interleukin-6 / G-CSF / MGF signature. / Interleukin-6/GCSF/MGF / Interleukin-6 homologues / Four-helical cytokine-like, core
Similarity search - Domain/homology
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.51 Å
AuthorsBukhdruker, S. / Yudenko, A. / Marin, E. / Remeeva, A. / Rodin, S. / Burtseva, A. / Petrov, A. / Ischenko, A. / Borshchevskiy, V.
Funding support Russian Federation, 1items
OrganizationGrant numberCountry
Ministry of Education and Science of the Russian Federation075-15-2021-1354 Russian Federation
CitationJournal: Structure / Year: 2025
Title: Structural basis of signaling complex inhibition by IL-6 domain-swapped dimers.
Authors: Yudenko, A. / Bukhdruker, S. / Shishkin, P. / Rodin, S. / Burtseva, A. / Petrov, A. / Pigareva, N. / Sokolov, A. / Zinovev, E. / Eliseev, I. / Remeeva, A. / Marin, E. / Mishin, A. / ...Authors: Yudenko, A. / Bukhdruker, S. / Shishkin, P. / Rodin, S. / Burtseva, A. / Petrov, A. / Pigareva, N. / Sokolov, A. / Zinovev, E. / Eliseev, I. / Remeeva, A. / Marin, E. / Mishin, A. / Gordeliy, V. / Gushchin, I. / Ischenko, A. / Borshchevskiy, V.
History
DepositionMar 31, 2024Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Nov 6, 2024Provider: repository / Type: Initial release
Revision 1.1Dec 4, 2024Group: Database references / Category: citation / citation_author
Item: _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed ..._citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.name
Revision 1.2Jan 15, 2025Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.year

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
H: Heavy chain of the Fab fragment of anti-IL-6 antibody I9H
L: Light chain of the Fab fragment of anti-IL-6 antibody I9H
A: Interleukin-6
hetero molecules


Theoretical massNumber of molelcules
Total (without water)69,3394
Polymers69,3153
Non-polymers241
Water543
1
H: Heavy chain of the Fab fragment of anti-IL-6 antibody I9H
L: Light chain of the Fab fragment of anti-IL-6 antibody I9H
A: Interleukin-6
hetero molecules

H: Heavy chain of the Fab fragment of anti-IL-6 antibody I9H
L: Light chain of the Fab fragment of anti-IL-6 antibody I9H
A: Interleukin-6
hetero molecules


Theoretical massNumber of molelcules
Total (without water)138,6798
Polymers138,6306
Non-polymers492
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_555-x,-y,z1
Unit cell
Length a, b, c (Å)126.621, 151.875, 76.053
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number21
Space group name H-MC222
Space group name HallC22
Symmetry operation#1: x,y,z
#2: x,-y,-z
#3: -x,y,-z
#4: -x,-y,z
#5: x+1/2,y+1/2,z
#6: x+1/2,-y+1/2,-z
#7: -x+1/2,y+1/2,-z
#8: -x+1/2,-y+1/2,z
Components on special symmetry positions
IDModelComponents
11A-501-

MG

21A-602-

HOH

31A-603-

HOH

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Components

#1: Antibody Heavy chain of the Fab fragment of anti-IL-6 antibody I9H


Mass: 24912.051 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Cricetulus griseus (Chinese hamster) / Strain (production host): CHO-IL69hum
#2: Antibody Light chain of the Fab fragment of anti-IL-6 antibody I9H


Mass: 23396.971 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Cricetulus griseus (Chinese hamster) / Strain (production host): CHO-IL69hum
#3: Protein Interleukin-6 / IL-6 / B-cell stimulatory factor 2 / BSF-2 / CTL differentiation factor / CDF / Hybridoma growth ...IL-6 / B-cell stimulatory factor 2 / BSF-2 / CTL differentiation factor / CDF / Hybridoma growth factor / Interferon beta-2 / IFN-beta-2


Mass: 21005.961 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: IL6, IFNB2 / Cell line (production host): HEK293 / Production host: Homo sapiens (human) / References: UniProt: P05231
#4: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 3 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestN
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: 2.63 Å3/Da / Density % sol: 53.28 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 10.5
Details: 40% v/v 2-methyl-2,4-pentanediol, 100 mM CAPS (seed stock crystallization conditions: 14-16% PEG 8000, 100 mM magnesium acetate, 100 mM MES pH 6.5)

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 0.85 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Nov 19, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.85 Å / Relative weight: 1
ReflectionResolution: 2.51→40.97 Å / Num. obs: 14890 / % possible obs: 91.7 % / Redundancy: 13 % / Biso Wilson estimate: 89.68 Å2 / CC1/2: 0.999 / Rpim(I) all: 0.031 / Net I/σ(I): 11.2
Reflection shellResolution: 2.51→2.82 Å / Redundancy: 12.3 % / Mean I/σ(I) obs: 0.7 / Num. unique obs: 744 / CC1/2: 0.098 / Rpim(I) all: 1.411 / % possible all: 69.3

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Processing

Software
NameVersionClassification
XDS20190315data reduction
STARANISO2.3.15data scaling
PHASER2.8.3phasing
PHENIX1.20.1_4487refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1ALU,8YWP

1alu

8ywp


Resolution: 2.51→40.97 Å / SU ML: 0.3274 / Cross valid method: FREE R-VALUE / σ(F): 1.33 / Phase error: 40.8304
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2774 1476 9.95 %
Rwork0.2394 13357 -
obs0.2432 14833 58.19 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 89.35 Å2
Refinement stepCycle: LAST / Resolution: 2.51→40.97 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4267 0 1 3 4271
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00184358
X-RAY DIFFRACTIONf_angle_d0.50835964
X-RAY DIFFRACTIONf_chiral_restr0.0396709
X-RAY DIFFRACTIONf_plane_restr0.0042762
X-RAY DIFFRACTIONf_dihedral_angle_d11.43011488
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.51-2.590.581970.478466X-RAY DIFFRACTION3.22
2.59-2.680.5314250.4848188X-RAY DIFFRACTION9.45
2.68-2.790.4928370.4927300X-RAY DIFFRACTION14.8
2.79-2.920.3445460.3986474X-RAY DIFFRACTION22.73
2.92-3.070.3713780.3807732X-RAY DIFFRACTION35.22
3.07-3.260.43781260.37861195X-RAY DIFFRACTION57.86
3.26-3.520.38812160.34511941X-RAY DIFFRACTION93.26
3.52-3.870.30212290.27392052X-RAY DIFFRACTION99.09
3.87-4.430.28772370.22472090X-RAY DIFFRACTION99.96
4.43-5.580.23862320.20632116X-RAY DIFFRACTION99.96
5.58-40.970.23812430.20382203X-RAY DIFFRACTION99.15
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)
11.062012057870.4877016250830.5883319529681.099751320560.9417013450842.19498917260.3843298238030.549722195222-0.403456778654-0.3527753205180.386430285456-0.316762450535-0.05135564312440.1889996136662.100260181210.363500864802-0.153683674677-0.286914570110.157426276793-0.2307464065630.258940975725-26.3534020568-20.666676001329.7318912311
20.8175513693250.161853616020.04828931153191.032207753510.07691273787640.3676460558680.173797097566-0.32015970918-0.166640779374-0.0256223101336-0.1405239452140.143029137536-0.0375608126131-0.855979141939-4.81735788323E-50.449597315974-0.0567398089341-0.09209712940910.8685143134120.009355039326920.460088489264-43.581003264-19.840104661936.7376925256
31.485482038010.236302297120.4846799011940.748496821365-0.1543764927892.059302356830.4872149904850.181828520009-0.2037410117040.2434244146810.200758650030.004953617519320.171125182712-0.1159310142790.9071475069440.3376633902530.0489904332561-0.00898518337880.213477146353-0.03560815685790.366643760953-1.82236941127-1.2168791146463.1008095693
Refinement TLS group

Refine-ID: X-RAY DIFFRACTION

IDRefine TLS-IDSelection detailsAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11(chain 'H' and resid 1 through 225)HA1 - 2251 - 218
22(chain 'L' and resid 1 through 213)LB1 - 2131 - 213
33(chain 'A' and resid 19 through 184)AC19 - 1841 - 148

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