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- PDB-8upa: Structure of gp130 in complex with a de novo designed IL-6 mimetic -

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Basic information

Entry
Database: PDB / ID: 8upa
TitleStructure of gp130 in complex with a de novo designed IL-6 mimetic
Components
  • De novo designed IL-6 mimetic
  • Interleukin-6 receptor subunit beta
KeywordsCYTOKINE / cytokine receptor / de novo design
Function / homology
Function and homology information


oncostatin-M-mediated signaling pathway / interleukin-27 receptor activity / ciliary neurotrophic factor receptor activity / leukemia inhibitory factor signaling pathway / negative regulation of interleukin-6-mediated signaling pathway / oncostatin-M receptor complex / ciliary neurotrophic factor receptor binding / interleukin-11 receptor activity / interleukin-11 binding / ciliary neurotrophic factor-mediated signaling pathway ...oncostatin-M-mediated signaling pathway / interleukin-27 receptor activity / ciliary neurotrophic factor receptor activity / leukemia inhibitory factor signaling pathway / negative regulation of interleukin-6-mediated signaling pathway / oncostatin-M receptor complex / ciliary neurotrophic factor receptor binding / interleukin-11 receptor activity / interleukin-11 binding / ciliary neurotrophic factor-mediated signaling pathway / ciliary neurotrophic factor receptor complex / interleukin-27-mediated signaling pathway / interleukin-6 receptor complex / interleukin-11-mediated signaling pathway / T-helper 17 cell lineage commitment / positive regulation of adaptive immune response / positive regulation of acute inflammatory response / positive regulation of astrocyte differentiation / intestinal epithelial cell development / positive regulation of platelet aggregation / Interleukin-27 signaling / IL-6-type cytokine receptor ligand interactions / Interleukin-35 Signalling / cytokine receptor activity / glycogen metabolic process / Interleukin-6 signaling / interleukin-6-mediated signaling pathway / positive regulation of Notch signaling pathway / protein tyrosine kinase activator activity / positive regulation of cardiac muscle hypertrophy / MAPK3 (ERK1) activation / growth factor binding / cytokine binding / MAPK1 (ERK2) activation / positive regulation of vascular endothelial growth factor production / positive regulation of osteoblast differentiation / coreceptor activity / positive regulation of T cell proliferation / positive regulation of tyrosine phosphorylation of STAT protein / response to cytokine / cytokine-mediated signaling pathway / scaffold protein binding / negative regulation of neuron apoptotic process / receptor complex / membrane raft / external side of plasma membrane / neuronal cell body / dendrite / positive regulation of cell population proliferation / negative regulation of apoptotic process / extracellular space / extracellular exosome / extracellular region / identical protein binding / membrane / plasma membrane
Similarity search - Function
Type I cytokine receptor, cytokine-binding domain / Interleukin-6 receptor alpha chain, binding / Immunoglobulin C2-set-like, ligand-binding / Ig-like C2-type domain / Long hematopoietin receptor, Gp130 family 2, conserved site / Long hematopoietin receptor, gp130 family signature. / : / Fibronectin type III domain / Fibronectin type 3 domain / Fibronectin type-III domain profile. ...Type I cytokine receptor, cytokine-binding domain / Interleukin-6 receptor alpha chain, binding / Immunoglobulin C2-set-like, ligand-binding / Ig-like C2-type domain / Long hematopoietin receptor, Gp130 family 2, conserved site / Long hematopoietin receptor, gp130 family signature. / : / Fibronectin type III domain / Fibronectin type 3 domain / Fibronectin type-III domain profile. / Fibronectin type III / Fibronectin type III superfamily / Immunoglobulin-like fold
Similarity search - Domain/homology
PHOSPHATE ION / Interleukin-6 receptor subunit beta
Similarity search - Component
Biological speciesHomo sapiens (human)
synthetic construct (others)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.3 Å
AuthorsBorowska, M.T. / Jude, K.M. / Garcia, K.C.
Funding support United States, 3items
OrganizationGrant numberCountry
Howard Hughes Medical Institute (HHMI) United States
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)RO1-AI51321 United States
The Mark Foundation United States
CitationJournal: Nat Commun / Year: 2024
Title: De novo design of miniprotein antagonists of cytokine storm inducers.
Authors: Huang, B. / Coventry, B. / Borowska, M.T. / Arhontoulis, D.C. / Exposit, M. / Abedi, M. / Jude, K.M. / Halabiya, S.F. / Allen, A. / Cordray, C. / Goreshnik, I. / Ahlrichs, M. / Chan, S. / ...Authors: Huang, B. / Coventry, B. / Borowska, M.T. / Arhontoulis, D.C. / Exposit, M. / Abedi, M. / Jude, K.M. / Halabiya, S.F. / Allen, A. / Cordray, C. / Goreshnik, I. / Ahlrichs, M. / Chan, S. / Tunggal, H. / DeWitt, M. / Hyams, N. / Carter, L. / Stewart, L. / Fuller, D.H. / Mei, Y. / Garcia, K.C. / Baker, D.
History
DepositionOct 22, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 28, 2024Provider: repository / Type: Initial release
Revision 1.1Oct 30, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: De novo designed IL-6 mimetic
B: Interleukin-6 receptor subunit beta
C: De novo designed IL-6 mimetic
D: Interleukin-6 receptor subunit beta
hetero molecules


Theoretical massNumber of molelcules
Total (without water)60,5379
Polymers59,5574
Non-polymers9805
Water362
1
A: De novo designed IL-6 mimetic
B: Interleukin-6 receptor subunit beta
hetero molecules


Theoretical massNumber of molelcules
Total (without water)30,3165
Polymers29,7792
Non-polymers5373
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2210 Å2
ΔGint-12 kcal/mol
Surface area13660 Å2
MethodPISA
2
C: De novo designed IL-6 mimetic
D: Interleukin-6 receptor subunit beta
hetero molecules


Theoretical massNumber of molelcules
Total (without water)30,2214
Polymers29,7792
Non-polymers4422
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1980 Å2
ΔGint-9 kcal/mol
Surface area14130 Å2
MethodPISA
Unit cell
Length a, b, c (Å)189.464, 189.464, 189.464
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number199
Space group name H-MI213

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Components

#1: Protein De novo designed IL-6 mimetic


Mass: 6656.609 Da / Num. of mol.: 2 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)
#2: Protein Interleukin-6 receptor subunit beta


Mass: 23121.949 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: IL6ST / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: P40189
#3: 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.: 4 / Source method: obtained synthetically / 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
#4: Chemical ChemComp-PO4 / PHOSPHATE ION


Mass: 94.971 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: PO4
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 2 / 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: 4.77 Å3/Da / Density % sol: 74.2 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop
Details: 0.04M Potassium phosphate monobasic, 16% Polyethylene glycol 8,000, 20% Glycerol

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 23-ID-D / Wavelength: 1.033149 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Oct 22, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.033149 Å / Relative weight: 1
ReflectionResolution: 3.3→29.96 Å / Num. obs: 32821 / % possible obs: 99.45 % / Redundancy: 1.9 % / CC1/2: 0.994 / Net I/σ(I): 11.16
Reflection shellResolution: 3.3→3.421 Å / Num. unique obs: 1660 / CC1/2: 0.669

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Processing

Software
NameVersionClassification
PHENIX(1.20_4459: ???)refinement
iMOSFLMdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 3.3→29.96 Å / SU ML: 0.49 / Cross valid method: FREE R-VALUE / σ(F): 1.33 / Phase error: 25.95 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2361 3296 10.06 %
Rwork0.1928 --
obs0.1971 32762 99.38 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 3.3→29.96 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4070 0 61 2 4133
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.003
X-RAY DIFFRACTIONf_angle_d0.568
X-RAY DIFFRACTIONf_dihedral_angle_d15.0931584
X-RAY DIFFRACTIONf_chiral_restr0.042640
X-RAY DIFFRACTIONf_plane_restr0.003729
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
3.3-3.350.50451220.35731093X-RAY DIFFRACTION87
3.35-3.40.38761440.34131238X-RAY DIFFRACTION100
3.4-3.450.36331320.32761216X-RAY DIFFRACTION100
3.45-3.510.33071420.31261261X-RAY DIFFRACTION100
3.51-3.570.31971380.28941250X-RAY DIFFRACTION100
3.57-3.630.33531400.29791189X-RAY DIFFRACTION100
3.64-3.70.36751370.29251230X-RAY DIFFRACTION100
3.71-3.780.35581360.2691257X-RAY DIFFRACTION100
3.78-3.860.27281380.25611198X-RAY DIFFRACTION100
3.86-3.950.30731400.25951221X-RAY DIFFRACTION100
3.95-4.050.28211360.23191256X-RAY DIFFRACTION100
4.05-4.160.19551400.18851214X-RAY DIFFRACTION100
4.16-4.280.25951280.18821287X-RAY DIFFRACTION100
4.28-4.420.19811340.1741236X-RAY DIFFRACTION100
4.42-4.580.21071380.16141232X-RAY DIFFRACTION100
4.58-4.760.2051360.1511242X-RAY DIFFRACTION100
4.76-4.970.18671400.15861232X-RAY DIFFRACTION100
4.98-5.230.21091400.15271242X-RAY DIFFRACTION100
5.24-5.560.20291390.15981191X-RAY DIFFRACTION100
5.56-5.990.24411350.16831247X-RAY DIFFRACTION100
5.99-6.580.25711440.18451235X-RAY DIFFRACTION100
6.59-7.520.16471400.17841237X-RAY DIFFRACTION100
7.54-9.430.18481400.14791234X-RAY DIFFRACTION100
9.45-29.960.17321370.14581228X-RAY DIFFRACTION99
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)
14.2031-2.07431.45291.65080.0361.31860.2725-0.1305-0.72590.2378-0.2234-0.41970.31390.3106-0.05681.1567-0.1072-0.12381.17650.32081.24158.949715.7458-21.937
24.7166-0.4566-1.28253.1304-0.20317.58240.14590.0640.0310.1743-0.1469-0.0410.2488-0.39460.01660.7809-0.02420.02160.8292-0.00040.7688-49.62874.5443-38.7569
30.2406-0.28580.3013.705-1.79891.1198-0.0171-0.02030.01820.0407-0.0423-0.1687-0.00610.09010.0550.8371-0.0110.06740.862-0.00490.6813-29.57418.2935-33.1156
44.75070.5763-0.51736.33660.30672.85620.2154-1.130.04581.018-0.5724-1.10530.02010.6330.14191.1504-0.2648-0.14771.4290.16490.981217.966338.2928-25.2095
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1(chain 'D' )
2X-RAY DIFFRACTION2(chain 'A' )
3X-RAY DIFFRACTION3(chain 'B' )
4X-RAY DIFFRACTION4(chain 'C' )

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