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- PDB-4zs7: Structural mimicry of receptor interaction by antagonistic IL-6 a... -

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Basic information

Entry
Database: PDB / ID: 4zs7
TitleStructural mimicry of receptor interaction by antagonistic IL-6 antibodies
Components
  • Interleukin-6Interleukin 6
  • Llama Fab fragment 68F2 heavy chain
  • Llama Fab fragment 68F2 light chain
KeywordsIMMUNE SYSTEM / Interleukine 6 Complex / Fab fragment / Dromedery
Function / homology
Function and homology information


positive regulation of interleukin-21 production / regulation of astrocyte activation / glucagon secretion / negative regulation of interleukin-1-mediated signaling pathway / hepatic immune response / regulation of glucagon secretion / regulation of vascular endothelial growth factor production / negative regulation of primary miRNA processing / T follicular helper cell differentiation / germinal center B cell differentiation ...positive regulation of interleukin-21 production / regulation of astrocyte activation / glucagon secretion / negative regulation of interleukin-1-mediated signaling pathway / hepatic immune response / regulation of glucagon secretion / regulation of vascular endothelial growth factor production / negative regulation of primary miRNA processing / T follicular helper cell differentiation / germinal center B cell differentiation / regulation of microglial cell activation / interleukin-6 receptor complex / positive regulation of extracellular matrix disassembly / positive regulation of receptor signaling pathway via STAT / positive regulation of type B pancreatic cell apoptotic process / positive regulation of apoptotic DNA fragmentation / response to peptidoglycan / hepatocyte proliferation / neutrophil apoptotic process / interleukin-6 receptor binding / negative regulation of collagen biosynthetic process / inflammatory response to wounding / T-helper 17 cell lineage commitment / positive regulation of T-helper 2 cell cytokine production / positive regulation of B cell activation / endocrine pancreas development / positive regulation of acute inflammatory response / regulation of neuroinflammatory response / vascular endothelial growth factor production / negative regulation of chemokine production / 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 / negative regulation of bone resorption / CD163 mediating an anti-inflammatory response / positive regulation of leukocyte adhesion to vascular endothelial cell / negative regulation of fat cell differentiation / maintenance of blood-brain barrier / Interleukin-6 signaling / interleukin-6-mediated signaling pathway / positive regulation of interleukin-17 production / MAPK3 (ERK1) activation / Interleukin-10 signaling / monocyte chemotaxis / MAPK1 (ERK2) activation / positive regulation of interleukin-10 production / regulation of insulin secretion / humoral immune response / negative regulation of lipid storage / positive regulation of immunoglobulin production / Transcriptional Regulation by VENTX / positive regulation of vascular endothelial growth factor production / positive regulation of epithelial to mesenchymal transition / positive regulation of osteoblast differentiation / regulation of angiogenesis / positive regulation of chemokine production / positive regulation of glial cell proliferation / response to glucocorticoid / positive regulation of tyrosine phosphorylation of STAT protein / positive regulation of T cell proliferation / positive regulation of translation / response to activity / positive regulation of interleukin-1 beta production / cytokine activity / liver regeneration / positive regulation of interleukin-8 production / Post-translational protein phosphorylation / acute-phase response / positive regulation of smooth muscle cell proliferation / positive regulation of receptor signaling pathway via JAK-STAT / growth factor activity / cellular response to hydrogen peroxide / platelet activation / cellular response to virus / ADORA2B mediated anti-inflammatory cytokines production / negative regulation of neurogenesis / positive regulation of interleukin-6 production / neuron cellular homeostasis / cytokine-mediated signaling pathway / Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) / neuron projection development / positive regulation of DNA-binding transcription factor activity / positive regulation of peptidyl-tyrosine phosphorylation / positive regulation of tumor necrosis factor production / glucose homeostasis / positive regulation of peptidyl-serine phosphorylation / Senescence-Associated Secretory Phenotype (SASP) / defense response to virus / Interleukin-4 and Interleukin-13 signaling / cellular response to lipopolysaccharide / defense response to Gram-negative bacterium / positive regulation of MAPK cascade / defense response to Gram-positive bacterium / inflammatory response / positive regulation of apoptotic process / endoplasmic reticulum lumen / negative regulation of cell population proliferation / positive regulation of cell population proliferation
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 / Growth Hormone; Chain: A; - #10 / Four-helical cytokine-like, core / Growth Hormone; Chain: A; / Immunoglobulins ...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 / Growth Hormone; Chain: A; - #10 / Four-helical cytokine-like, core / Growth Hormone; Chain: A; / Immunoglobulins / Up-down Bundle / Immunoglobulin-like / Sandwich / Mainly Beta / Mainly Alpha
Similarity search - Domain/homology
Biological speciesHomo sapiens (human)
Lama glama (llama)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 2.93 Å
AuthorsBlanchetot, C. / De Jonge, N. / Desmyter, A. / Ongenae, N. / Hofman, E. / Klarenbeek, A. / Sadi, A. / Hultberg, A. / Kretz-Rommel, A. / Spinelli, S. ...Blanchetot, C. / De Jonge, N. / Desmyter, A. / Ongenae, N. / Hofman, E. / Klarenbeek, A. / Sadi, A. / Hultberg, A. / Kretz-Rommel, A. / Spinelli, S. / Loris, R. / Cambillau, C. / de Haard, H.
CitationJournal: J.Biol.Chem. / Year: 2016
Title: Structural Mimicry of Receptor Interaction by Antagonistic Interleukin-6 (IL-6) Antibodies.
Authors: Blanchetot, C. / De Jonge, N. / Desmyter, A. / Ongenae, N. / Hofman, E. / Klarenbeek, A. / Sadi, A. / Hultberg, A. / Kretz-Rommel, A. / Spinelli, S. / Loris, R. / Cambillau, C. / de Haard, H.
History
DepositionMay 13, 2015Deposition site: RCSB / Processing site: PDBE
Revision 1.0May 4, 2016Provider: repository / Type: Initial release
Revision 1.1May 11, 2016Group: Database references
Revision 1.2Jul 6, 2016Group: Database references

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Interleukin-6
H: Llama Fab fragment 68F2 heavy chain
L: Llama Fab fragment 68F2 light chain


Theoretical massNumber of molelcules
Total (without water)66,4423
Polymers66,4423
Non-polymers00
Water1,44180
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5850 Å2
ΔGint-16 kcal/mol
Surface area25930 Å2
MethodPISA
Unit cell
Length a, b, c (Å)46.550, 92.860, 84.630
Angle α, β, γ (deg.)90.00, 103.93, 90.00
Int Tables number3
Space group name H-MP121

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Components

#1: Protein Interleukin-6 / 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: 19670.518 Da / Num. of mol.: 1 / Fragment: residues 14-184
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: IL6, IFNB2 / Production host: Escherichia coli (E. coli) / References: UniProt: P05231
#2: Antibody Llama Fab fragment 68F2 heavy chain


Mass: 23822.410 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Lama glama (llama) / Production host: Lama glama (llama)
#3: Antibody Llama Fab fragment 68F2 light chain


Mass: 22949.469 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Lama glama (llama) / Production host: Lama glama (llama)
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 80 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 2.82 Å3/Da / Density % sol: 53.97 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 5.5
Details: 25% PEG 4K, 0.15 M (NH4)2SO4, 0.1 M MES pH 5.5. Took 9 month

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID14-4 / Wavelength: 0.971 Å
DetectorType: ADSC QUANTUM 4 / Detector: CCD / Date: Jul 27, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.971 Å / Relative weight: 1
ReflectionResolution: 2.93→45 Å / Num. obs: 14778 / % possible obs: 97.9 % / Observed criterion σ(I): 0 / Redundancy: 6.5 % / Biso Wilson estimate: 45.64 Å2 / Rmerge(I) obs: 0.18 / Net I/σ(I): 7.5
Reflection shellResolution: 2.93→3 Å / Redundancy: 5.2 % / Rmerge(I) obs: 0.8 / % possible all: 88.8

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Processing

Software
NameVersionClassification
BUSTER2.11.2refinement
XDSdata reduction
XSCALEdata scaling
MOLREPphasing
RefinementResolution: 2.93→44.35 Å / Cor.coef. Fo:Fc: 0.7636 / Cor.coef. Fo:Fc free: 0.7153 / Cross valid method: THROUGHOUT / σ(F): 0 / SU Rfree Blow DPI: 0.46
RfactorNum. reflection% reflectionSelection details
Rfree0.293 1490 10.08 %RANDOM
Rwork0.2613 ---
obs0.2645 14778 97.6 %-
Displacement parametersBiso mean: 30.46 Å2
Baniso -1Baniso -2Baniso -3
1-12.8 Å20 Å2-1.5455 Å2
2--7.1439 Å20 Å2
3----19.9439 Å2
Refine analyzeLuzzati coordinate error obs: 0.503 Å
Refinement stepCycle: 1 / Resolution: 2.93→44.35 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4374 0 0 80 4454
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0084476HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.326095HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1487SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes96HARMONIC2
X-RAY DIFFRACTIONt_gen_planes642HARMONIC5
X-RAY DIFFRACTIONt_it4476HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.37
X-RAY DIFFRACTIONt_other_torsion23.9
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion605SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact4975SEMIHARMONIC4
LS refinement shellResolution: 2.93→3.17 Å / Total num. of bins used: 7
RfactorNum. reflection% reflection
Rfree0.3422 289 9.99 %
Rwork0.2721 2604 -
all0.279 2893 -
obs--97.6 %
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)
10.09270.02680.04880.1392-0.04140.16330.00060.0006-0.0001-0.001-0.00030.00110.0003-0.0008-0.00030.00440.0004-0.00150.0052-0.00110.002216.609734.593416.4177
20.08940.024-0.05680.06550.1081-0.0337-0.0006-0.0002-0.00170.00050.0010.00120.0023-0.0003-0.00040.0003-0.0002-0.00010.003-0.00010.00012.27049.604821.5744
30.1317-0.0819-0.02850.05340.00710.0589-0.00040.0005-0.0006-0.00030.0004-0.00010.00010.001200.0008-0.0009-0.0010.00370.0013-0.000729.822725.805231.004
40.0921-0.009-0.05470.1247-0.01550.0949-0.00030.0009-0.001-0.00190.00050.00080.0026-0.0012-0.00020.0037-0.0001-0.00320.0007-0.00320.00129.6701-6.151421.2035
5-0.0094-0.0240.01790-0.07020.009400.00060.0021-0.001500.0009-0.0027-0.0010-0.0071-0.00040.0021-0.0071-0.0003-0.002630.095558.525220.1803
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1{H|1 - H|109}
2X-RAY DIFFRACTION2{H|110 - H|222}
3X-RAY DIFFRACTION3{L|3 - L|109}
4X-RAY DIFFRACTION4{L|110 - L|212}
5X-RAY DIFFRACTION5{A|23 - A|184}

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