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- PDB-5fuc: Biophysical and cellular characterisation of a junctional epitope... -

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Basic information

Entry
Database: PDB / ID: 5fuc
TitleBiophysical and cellular characterisation of a junctional epitope antibody that locks IL-6 and gp80 together in a stable complex: implications for new therapeutic strategies
Components
  • INTERLEUKIN-6 RECEPTOR SUBUNIT ALPHA, INTERLEUKIN-6 RECEPTOR
  • INTERLEUKIN-6Interleukin 6
  • VHH6
KeywordsIMMUNE SYSTEM / VHH / IL-6 / IL-6 RECEPTOR ALPHA / IL-6 RECEPTOR BETA / GP80 / ANTIBODY / JUNCTIONAL EPITOPE
Function / homology
Function and homology information


ciliary neurotrophic factor binding / positive regulation of interleukin-21 production / regulation of astrocyte activation / glucagon secretion / interleukin-6 receptor activity / interleukin-6 binding / regulation of glucagon secretion / negative regulation of interleukin-1-mediated signaling pathway / hepatic immune response / regulation of vascular endothelial growth factor production ...ciliary neurotrophic factor binding / positive regulation of interleukin-21 production / regulation of astrocyte activation / glucagon secretion / interleukin-6 receptor activity / interleukin-6 binding / regulation of glucagon secretion / negative regulation of interleukin-1-mediated signaling pathway / hepatic immune response / regulation of vascular endothelial growth factor production / negative regulation of primary miRNA processing / T follicular helper cell differentiation / interleukin-11 receptor activity / interleukin-11 binding / germinal center B cell differentiation / ciliary neurotrophic factor receptor complex / regulation of microglial cell activation / ciliary neurotrophic factor-mediated signaling pathway / interleukin-6 receptor complex / positive regulation of extracellular matrix disassembly / positive regulation of type B pancreatic cell apoptotic process / positive regulation of receptor signaling pathway via STAT / positive regulation of apoptotic DNA fragmentation / response to peptidoglycan / hepatocyte proliferation / neutrophil apoptotic process / interleukin-6 receptor binding / negative regulation of collagen biosynthetic process / positive regulation of activation of Janus kinase activity / 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 / positive regulation of glomerular mesangial cell proliferation / endocrine pancreas development / negative regulation of interleukin-8 production / 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 / cytokine receptor activity / 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 / MAPK1 (ERK2) activation / monocyte chemotaxis / 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 / extrinsic apoptotic signaling pathway / 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 / response to cytokine / cytokine activity / liver regeneration / positive regulation of interleukin-8 production / acute-phase response / Post-translational protein phosphorylation / 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 / neuron cellular homeostasis / cytokine-mediated signaling pathway / positive regulation of interleukin-6 production / Transcriptional regulation of granulopoiesis / 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 / glucose homeostasis
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 / Type I cytokine receptor, cytokine-binding domain / Interleukin-6 receptor alpha chain, binding / Long hematopoietin receptor, soluble alpha chain, conserved site / Long hematopoietin receptor, soluble alpha chains family signature. ...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 / Type I cytokine receptor, cytokine-binding domain / Interleukin-6 receptor alpha chain, binding / Long hematopoietin receptor, soluble alpha chain, conserved site / Long hematopoietin receptor, soluble alpha chains family signature. / Growth Hormone; Chain: A; - #10 / Four-helical cytokine-like, core / Growth Hormone; Chain: A; / Immunoglobulin / Immunoglobulin domain / Fibronectin type 3 domain / Immunoglobulin subtype 2 / Immunoglobulin C-2 Type / Fibronectin type-III domain profile. / Fibronectin type III / Fibronectin type III superfamily / Immunoglobulin subtype / Immunoglobulin / Ig-like domain profile. / Immunoglobulin-like domain / Immunoglobulin-like domain superfamily / Immunoglobulins / Immunoglobulin-like fold / Up-down Bundle / Immunoglobulin-like / Sandwich / Mainly Beta / Mainly Alpha
Similarity search - Domain/homology
Interleukin-6 receptor subunit alpha / Interleukin-6 / Interleukin-6 receptor subunit alpha
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
CAMELUS DROMEDARIUS (Arabian camel)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.7 Å
AuthorsAdams, R. / Griffin, R. / Doyle, C. / Ettorre, A.
CitationJournal: Sci Rep / Year: 2017
Title: Discovery of a junctional epitope antibody that stabilizes IL-6 and gp80 protein:protein interaction and modulates its downstream signaling.
Authors: Adams, R. / Burnley, R.J. / Valenzano, C.R. / Qureshi, O. / Doyle, C. / Lumb, S. / Del Carmen Lopez, M. / Griffin, R. / McMillan, D. / Taylor, R.D. / Meier, C. / Mori, P. / Griffin, L.M. / ...Authors: Adams, R. / Burnley, R.J. / Valenzano, C.R. / Qureshi, O. / Doyle, C. / Lumb, S. / Del Carmen Lopez, M. / Griffin, R. / McMillan, D. / Taylor, R.D. / Meier, C. / Mori, P. / Griffin, L.M. / Wernery, U. / Kinne, J. / Rapecki, S. / Baker, T.S. / Lawson, A.D. / Wright, M. / Ettorre, A.
History
DepositionJan 25, 2016Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jan 25, 2017Provider: repository / Type: Initial release
Revision 1.1Mar 1, 2017Group: Database references
Revision 1.2Apr 3, 2019Group: Advisory / Data collection ...Advisory / Data collection / Derived calculations / Source and taxonomy
Category: entity_src_gen / pdbx_seq_map_depositor_info ...entity_src_gen / pdbx_seq_map_depositor_info / pdbx_unobs_or_zero_occ_atoms / struct_conn
Item: _entity_src_gen.pdbx_host_org_cell_line / _pdbx_seq_map_depositor_info.one_letter_code ..._entity_src_gen.pdbx_host_org_cell_line / _pdbx_seq_map_depositor_info.one_letter_code / _pdbx_seq_map_depositor_info.one_letter_code_mod / _struct_conn.pdbx_leaving_atom_flag
Revision 1.3Jul 29, 2020Group: Data collection / Derived calculations ...Data collection / Derived calculations / Other / Structure summary
Category: chem_comp / entity ...chem_comp / entity / pdbx_chem_comp_identifier / pdbx_database_status / pdbx_entity_nonpoly / reflns_shell / struct_conn / struct_site / struct_site_gen
Item: _chem_comp.name / _chem_comp.type ..._chem_comp.name / _chem_comp.type / _entity.pdbx_description / _pdbx_database_status.status_code_sf / _pdbx_entity_nonpoly.name / _reflns_shell.Rmerge_I_obs / _struct_conn.pdbx_role
Description: Carbohydrate remediation / Provider: repository / Type: Remediation
Revision 1.4Jan 10, 2024Group: Advisory / Data collection ...Advisory / Data collection / Database references / Refinement description / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / pdbx_unobs_or_zero_occ_atoms
Item: _chem_comp.pdbx_synonyms / _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: INTERLEUKIN-6
B: INTERLEUKIN-6
C: INTERLEUKIN-6 RECEPTOR SUBUNIT ALPHA, INTERLEUKIN-6 RECEPTOR
D: INTERLEUKIN-6 RECEPTOR SUBUNIT ALPHA, INTERLEUKIN-6 RECEPTOR
E: VHH6
V: VHH6
hetero molecules


Theoretical massNumber of molelcules
Total (without water)120,15110
Polymers119,2666
Non-polymers8854
Water2,000111
1
A: INTERLEUKIN-6
D: INTERLEUKIN-6 RECEPTOR SUBUNIT ALPHA, INTERLEUKIN-6 RECEPTOR
V: VHH6
hetero molecules


Theoretical massNumber of molelcules
Total (without water)60,0755
Polymers59,6333
Non-polymers4422
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4360 Å2
ΔGint-11.2 kcal/mol
Surface area31000 Å2
MethodPQS
2
B: INTERLEUKIN-6
C: INTERLEUKIN-6 RECEPTOR SUBUNIT ALPHA, INTERLEUKIN-6 RECEPTOR
E: VHH6
hetero molecules


Theoretical massNumber of molelcules
Total (without water)60,0755
Polymers59,6333
Non-polymers4422
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3680 Å2
ΔGint-10.8 kcal/mol
Surface area35330 Å2
MethodPQS
Unit cell
Length a, b, c (Å)249.030, 67.800, 78.160
Angle α, β, γ (deg.)90.00, 104.53, 90.00
Int Tables number5
Space group name H-MC121

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Components

#1: Protein INTERLEUKIN-6 / Interleukin 6 / IL-6 / B-CELL STIMULATORY FACTOR 2 / BSF-2 / IFN-BETA-2 / CTL DIFFERENTIATION FACTOR / CDF / ...IL-6 / B-CELL STIMULATORY FACTOR 2 / BSF-2 / IFN-BETA-2 / CTL DIFFERENTIATION FACTOR / CDF / HYBRIDOMA GROWTH FACTOR / INTERFERON BETA-2


Mass: 18982.682 Da / Num. of mol.: 2 / Fragment: RESIDUES 49-212
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Production host: ESCHERICHIA COLI (E. coli) / References: UniProt: P05231
#2: Protein INTERLEUKIN-6 RECEPTOR SUBUNIT ALPHA, INTERLEUKIN-6 RECEPTOR / / IL-6RA / IL-6R 1 / MEMBRANE GLYCOPROTEIN 80 / GP80


Mass: 25973.068 Da / Num. of mol.: 2 / Fragment: RESIDUES 20-33 AND RESIDUES 111-322 / Mutation: YES
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Cell line (production host): HEK293 / Production host: HOMO SAPIENS (human) / References: UniProt: D6R9R8, UniProt: P08887
#3: Antibody VHH6


Mass: 14677.187 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) CAMELUS DROMEDARIUS (Arabian camel) / Cell line (production host): HEK293 / Production host: HOMO SAPIENS (human)
#4: 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 / N-Acetylglucosamine


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Formula: C8H15NO6
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
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 111 / Source method: isolated from a natural source / Formula: H2O
Sequence detailsCYS 192 MUTATED TO SER, CYS 258 MUTATED TO ALA. THE FIRST 19 RESIDUES ARE FROM DOMAIN 1 OF IL-6. ...CYS 192 MUTATED TO SER, CYS 258 MUTATED TO ALA. THE FIRST 19 RESIDUES ARE FROM DOMAIN 1 OF IL-6. THE REST OF THE SEQUENCE IS DOMAIN 3. RENLYFQ IS REMAINDER OF TEV CLEAVAGE SITE VHH6 IS INTERNAL DISCOVERY

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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: 2.4 Å3/Da / Density % sol: 49 % / Description: NONE
Crystal growDetails: 0.1 M MES, PH 6.5, 14% PEG20K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SOLEIL / Beamline: PROXIMA 1 / Wavelength: 0.97857
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Sep 12, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97857 Å / Relative weight: 1
ReflectionResolution: 2.69→50 Å / Num. obs: 18151 / % possible obs: 99.4 % / Observed criterion σ(I): 3 / Redundancy: 7.5 % / Rmerge(I) obs: 0.07 / Net I/σ(I): 20.88
Reflection shellResolution: 2.69→2.86 Å / Redundancy: 7.5 % / Rmerge(I) obs: 0.5 / Mean I/σ(I) obs: 3.97 / % possible all: 96.9

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Processing

Software
NameVersionClassification
CNS1.3refinement
XDSdata reduction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1P9M, VHH IN-HOUSE STRUCTURE

1p9m


Resolution: 2.7→20 Å / Rfactor Rfree error: 0.005 / Data cutoff high absF: 10000 / Data cutoff low absF: 0 / Cross valid method: THROUGHOUT / σ(F): 0
Details: THE FOLLOWING REGIONS WERE TOO DISORDERED TO MODEL, CHAIN A RESIDUES 52 TO 62, 131 TO 133, CHAIN B RESIDUES 19 AND 20, 132 TO 135, CHAIN C RESIDUES 73 TO 97, 138, 298 TO 303, CHAIN D ...Details: THE FOLLOWING REGIONS WERE TOO DISORDERED TO MODEL, CHAIN A RESIDUES 52 TO 62, 131 TO 133, CHAIN B RESIDUES 19 AND 20, 132 TO 135, CHAIN C RESIDUES 73 TO 97, 138, 298 TO 303, CHAIN D RESIDUES 73 TO 91, 134 TO 140, 299 TO 303, CHAIN E RESIDUES 1 AND 2, 8 TO 16, 121 TO 132, CHAIN V RESIDUES 125 TO 132
RfactorNum. reflection% reflectionSelection details
Rfree0.2872 3461 9.9 %RANDOM
Rwork0.2313 ---
obs0.2313 34870 100 %-
Displacement parameters
Baniso -1Baniso -2Baniso -3
1-0.764 Å20 Å2-2.079 Å2
2---3.666 Å20 Å2
3---2.902 Å2
Refinement stepCycle: LAST / Resolution: 2.7→20 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7505 0 56 111 7672
LS refinement shellResolution: 2.7→2.8 Å / Rfactor Rfree error: 0.026 / Total num. of bins used: 10
RfactorNum. reflection% reflection
Rfree0.4847 342 9.9 %
Rwork0.4176 3117 -
obs--100 %

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