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- PDB-7kpb: Human TNF-alpha TNFR1 complex bound to conformationally selective... -

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Basic information

Entry
Database: PDB / ID: 7kpb
TitleHuman TNF-alpha TNFR1 complex bound to conformationally selective antibody
Components
  • (Tumor necrosis ...) x 2
  • Fab1974 - Heavy Chain
  • Fab1974 - Light Chain
KeywordsCYTOKINE/Immune System / Tumour necrosis factor alpha / TNF / asymmetric / protein-protein inhibitor / CYTOKINE / Fragment antibody / Fab / CYTOKINE-Immune System complex
Function / homology
Function and homology information


positive regulation of amide metabolic process / tumor necrosis factor receptor superfamily complex / pulmonary valve development / negative regulation of L-glutamate import across plasma membrane / negative regulation of bile acid secretion / response to Gram-negative bacterium / positive regulation of neutrophil activation / positive regulation of fractalkine production / negative regulation of branching involved in lung morphogenesis / positive regulation of interleukin-33 production ...positive regulation of amide metabolic process / tumor necrosis factor receptor superfamily complex / pulmonary valve development / negative regulation of L-glutamate import across plasma membrane / negative regulation of bile acid secretion / response to Gram-negative bacterium / positive regulation of neutrophil activation / positive regulation of fractalkine production / negative regulation of branching involved in lung morphogenesis / positive regulation of interleukin-33 production / positive regulation of lipid metabolic process / positive regulation of blood microparticle formation / aortic valve development / positive regulation of chronic inflammatory response to antigenic stimulus / tumor necrosis factor receptor activity / negative regulation of extracellular matrix constituent secretion / response to 3,3',5-triiodo-L-thyronine / positive regulation of protein transport / positive regulation of leukocyte adhesion to arterial endothelial cell / positive regulation of vitamin D biosynthetic process / positive regulation of apoptotic process involved in morphogenesis / positive regulation of translational initiation by iron / regulation of membrane lipid metabolic process / regulation of endothelial cell apoptotic process / chronic inflammatory response to antigenic stimulus / response to macrophage colony-stimulating factor / regulation of branching involved in salivary gland morphogenesis / negative regulation of protein-containing complex disassembly / positive regulation of humoral immune response mediated by circulating immunoglobulin / positive regulation of hair follicle development / negative regulation of myelination / response to gold nanoparticle / TNFs bind their physiological receptors / tumor necrosis factor binding / negative regulation of vascular wound healing / negative regulation of cytokine production involved in immune response / negative regulation of amyloid-beta clearance / positive regulation of interleukin-18 production / inflammatory response to wounding / negative regulation of cardiac muscle hypertrophy / death receptor agonist activity / positive regulation of action potential / TNF signaling / epithelial cell proliferation involved in salivary gland morphogenesis / toll-like receptor 3 signaling pathway / negative regulation of D-glucose import across plasma membrane / leukocyte migration involved in inflammatory response / vascular endothelial growth factor production / embryonic digestive tract development / positive regulation of fever generation / response to fructose / positive regulation of neuroinflammatory response / positive regulation of synoviocyte proliferation / positive regulation of calcineurin-NFAT signaling cascade / necroptotic signaling pathway / positive regulation of mononuclear cell migration / leukocyte tethering or rolling / positive regulation of hepatocyte proliferation / negative regulation of myoblast differentiation / positive regulation of protein-containing complex disassembly / regulation of establishment of endothelial barrier / endothelial cell apoptotic process / negative regulation of oxidative phosphorylation / regulation of tumor necrosis factor-mediated signaling pathway / cellular response to toxic substance / positive regulation of protein localization to cell surface / macrophage activation involved in immune response / positive regulation of osteoclast differentiation / negative regulation of systemic arterial blood pressure / tumor necrosis factor receptor binding / positive regulation of heterotypic cell-cell adhesion / positive regulation of macrophage derived foam cell differentiation / positive regulation of cytokine production involved in inflammatory response / regulation of immunoglobulin production / negative regulation of mitotic cell cycle / positive regulation of programmed cell death / TNFR1-mediated ceramide production / positive regulation of podosome assembly / positive regulation of membrane protein ectodomain proteolysis / positive regulation of chemokine (C-X-C motif) ligand 2 production / regulation of fat cell differentiation / regulation of canonical NF-kappaB signal transduction / response to L-glutamate / positive regulation of extrinsic apoptotic signaling pathway / positive regulation of leukocyte adhesion to vascular endothelial cell / TNFR1-induced proapoptotic signaling / regulation of metabolic process / regulation of reactive oxygen species metabolic process / positive regulation of DNA biosynthetic process / negative regulation of bicellular tight junction assembly / prostaglandin metabolic process / negative regulation of heart rate / positive regulation of amyloid-beta formation / negative regulation of viral genome replication / response to isolation stress / negative regulation of fat cell differentiation / regulation of synapse organization / negative regulation of endothelial cell proliferation / positive regulation of JUN kinase activity / positive regulation of MAP kinase activity
Similarity search - Function
Tumour necrosis factor receptor 1A / Tumor necrosis factor receptor 1A, N-terminal / Tumor necrosis factor receptor 1A, death domain / : / Tumour necrosis factor alpha / Tumour necrosis factor / Tumour necrosis factor, conserved site / Tumor necrosis factor (TNF) homology domain (THD) signature. / Tumour necrosis factor family. / TNFR/NGFR family cysteine-rich region domain profile. ...Tumour necrosis factor receptor 1A / Tumor necrosis factor receptor 1A, N-terminal / Tumor necrosis factor receptor 1A, death domain / : / Tumour necrosis factor alpha / Tumour necrosis factor / Tumour necrosis factor, conserved site / Tumor necrosis factor (TNF) homology domain (THD) signature. / Tumour necrosis factor family. / TNFR/NGFR family cysteine-rich region domain profile. / TNFR/NGFR cysteine-rich region / TNF(Tumour Necrosis Factor) family / TNFR/NGFR family cysteine-rich region signature. / Tumor necrosis factor receptor / nerve growth factor receptor repeats. / TNFR/NGFR cysteine-rich region / Tumour necrosis factor domain / Tumor necrosis factor (TNF) homology domain (THD) profile. / Tumour necrosis factor-like domain superfamily / Death domain profile. / DEATH domain, found in proteins involved in cell death (apoptosis). / Death domain / Death domain / Death-like domain superfamily / Immunoglobulins / Immunoglobulin-like / Sandwich / Mainly Beta
Similarity search - Domain/homology
Chem-D84 / Tumor necrosis factor / Tumor necrosis factor receptor superfamily member 1A
Similarity search - Component
Biological speciesHomo sapiens (human)
Mus musculus (house mouse)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3 Å
AuthorsFox III, D. / Conrady, D.G. / Lowe, M. / Ceska, T.
CitationJournal: Nat Commun / Year: 2021
Title: A conformation-selective monoclonal antibody against a small molecule-stabilised signalling-deficient form of TNF
Authors: Lightwood, D.J. / Munro, R.J. / Porter, J. / McMillan, D. / Carrington, B. / Turner, A. / Scott-Tucker, A. / Hickford, E.S. / Schmidt, A. / Fox III, D. / Maloney, A. / Ceska, T. / Bourne, T. ...Authors: Lightwood, D.J. / Munro, R.J. / Porter, J. / McMillan, D. / Carrington, B. / Turner, A. / Scott-Tucker, A. / Hickford, E.S. / Schmidt, A. / Fox III, D. / Maloney, A. / Ceska, T. / Bourne, T. / O'Connell, J. / Lawson, A.D.G.
History
DepositionNov 10, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 13, 2021Provider: repository / Type: Initial release
Revision 1.1Feb 3, 2021Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Jun 29, 2022Group: Database references / Structure summary / Category: citation_author / database_2 / struct
Item: _citation_author.name / _database_2.pdbx_DOI ..._citation_author.name / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct.title
Revision 1.3May 24, 2023Group: Database references / Structure summary / Category: citation / struct / Item: _citation.title / _struct.title
Revision 1.4Apr 3, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.5Oct 23, 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: Tumor necrosis factor
B: Tumor necrosis factor
C: Tumor necrosis factor
F: Tumor necrosis factor receptor superfamily member 1A
E: Tumor necrosis factor receptor superfamily member 1A
L: Fab1974 - Light Chain
H: Fab1974 - Heavy Chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)134,08818
Polymers132,4817
Non-polymers1,60711
Water36020
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)99.510, 99.510, 311.350
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number92
Space group name H-MP41212

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Components

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Tumor necrosis ... , 2 types, 5 molecules ABCFE

#1: Protein Tumor necrosis factor / Cachectin / TNF-alpha / Tumor necrosis factor ligand superfamily member 2 / TNF-a


Mass: 17457.736 Da / Num. of mol.: 3 / Mutation: N25D, C153S
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TNF, TNFA, TNFSF2 / Plasmid: pBAD_Smt3_Bam / Production host: Escherichia coli (E. coli) / References: UniProt: P01375
#2: Protein Tumor necrosis factor receptor superfamily member 1A / Tumor necrosis factor receptor 1 / TNF-R1 / Tumor necrosis factor receptor type I / TNFR-I / p55 / p60


Mass: 16196.158 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TNFRSF1A, TNFAR, TNFR1 / Plasmid: pEMB50 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: P19438

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Antibody , 2 types, 2 molecules LH

#3: Antibody Fab1974 - Light Chain


Mass: 23649.170 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Gene: mFab'nh CA_185_1974 / Cell line (production host): HEK293 / Production host: Homo sapiens (human)
#4: Antibody Fab1974 - Heavy Chain


Mass: 24066.783 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Gene: mFab'nh CA_185_1974 / Cell line (production host): HEK293 / Production host: Homo sapiens (human)

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Sugars , 1 types, 1 molecules

#7: 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.: 1 / 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

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Non-polymers , 3 types, 30 molecules

#5: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 9 / Source method: isolated from a natural source / Formula: C3H8O3
#6: Chemical ChemComp-D84 / 5-(1-{[2-(difluoromethoxy)phenyl]methyl}-2-{[3-(2-oxopyrrolidin-1-yl)phenoxy]methyl}-1H-benzimidazol-6-yl)pyridin-2(1H)-one


Mass: 556.559 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C31H26F2N4O4 / Feature type: SUBJECT OF INVESTIGATION
#8: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 20 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY
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: 2.91 Å3/Da / Density % sol: 57.72 %
Crystal growTemperature: 289 K / Method: vapor diffusion, sitting drop / pH: 7
Details: 0.1M HEPES, pH7.0, 10% w/v PEG6,000 and cryo-protected in glycerol performed in 5-10-15% steps. Vapor diffusion, sitting drop, temperature 289K
PH range: 7

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-F / Wavelength: 0.9787 Å
DetectorType: MARMOSAIC 300 mm CCD / Detector: CCD / Date: Jun 8, 2016 / Details: Beryllium Lenses
RadiationMonochromator: Diamond [111] / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9787 Å / Relative weight: 1
ReflectionResolution: 3→50 Å / Num. obs: 32445 / % possible obs: 99.9 % / Observed criterion σ(I): -3 / Redundancy: 12.1 % / Biso Wilson estimate: 71.095 Å2 / CC1/2: 0.996 / Rmerge(I) obs: 0.163 / Rrim(I) all: 0.171 / Χ2: 0.958 / Net I/σ(I): 13.95
Reflection shell

Diffraction-ID: 1

Resolution (Å)Rmerge(I) obsMean I/σ(I) obsNum. unique obsCC1/2Rrim(I) all% possible all
3-3.081.3962.0623330.7141.457100
3.08-3.160.9882.9222740.8061.031100
3.16-3.250.7593.6922350.8990.792100
3.25-3.350.5954.6921710.9230.62100
3.35-3.460.4446.2420840.9540.463100
3.46-3.590.3467.9220480.970.361100
3.59-3.720.289.519760.980.292100
3.72-3.870.2211.7318860.9870.23100
3.87-4.050.17913.7518340.9910.186100
4.05-4.240.1416.9717440.9940.146100
4.24-4.470.11320.416780.9960.118100
4.47-4.740.09822.8616110.9960.102100
4.74-5.070.09423.8714860.9960.09899.9
5.07-5.480.09623.4314040.9970.1100
5.48-60.09622.5413020.9970.1100
6-6.710.08924.4812040.9970.093100
6.71-7.750.07726.8810600.9980.081100
7.75-9.490.06132.089180.9980.064100
9.49-13.420.05236.437380.9980.055100
13.42-500.05324590.9950.05496

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Processing

Software
NameVersionClassification
PHENIXdev_2443refinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: unpublished structure

Resolution: 3→49.132 Å / SU ML: 0.41 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 25.73 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2555 1615 4.99 %
Rwork0.2229 30727 -
obs0.2246 32342 99.94 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 175.92 Å2 / Biso mean: 69.5983 Å2 / Biso min: 23.1 Å2
Refinement stepCycle: final / Resolution: 3→49.132 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8376 0 109 20 8505
Biso mean--64.03 47.65 -
Num. residues----1141
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0038728
X-RAY DIFFRACTIONf_angle_d0.5711927
X-RAY DIFFRACTIONf_chiral_restr0.0441316
X-RAY DIFFRACTIONf_plane_restr0.0041557
X-RAY DIFFRACTIONf_dihedral_angle_d12.0275193
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
3-3.08830.36731310.34132504X-RAY DIFFRACTION100
3.0883-3.1880.35131320.29532502X-RAY DIFFRACTION100
3.188-3.30190.32011320.28842515X-RAY DIFFRACTION100
3.3019-3.43410.29091330.25742517X-RAY DIFFRACTION100
3.4341-3.59030.26921330.25262506X-RAY DIFFRACTION100
3.5903-3.77950.27721320.23462524X-RAY DIFFRACTION100
3.7795-4.01620.26641340.21822535X-RAY DIFFRACTION100
4.0162-4.32620.22561350.20162563X-RAY DIFFRACTION100
4.3262-4.76120.22731340.18442558X-RAY DIFFRACTION100
4.7612-5.44940.20791360.18492587X-RAY DIFFRACTION100
5.4494-6.86270.23941380.21482622X-RAY DIFFRACTION100
6.8627-49.1320.25511450.21732794X-RAY DIFFRACTION99

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