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- PDB-6op0: Asymmetric hTNF-alpha -

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Basic information

Entry
Database: PDB / ID: 6op0
TitleAsymmetric hTNF-alpha
ComponentsTumor necrosis factor
KeywordsCYTOKINE / Tumour necrosis factor alpha / TNF / asymmetric / protein-protein interaction inhibitor / rheumatoid arthritis
Function / homology
Function and homology information


response to Gram-negative bacterium / negative regulation of L-glutamate import across plasma membrane / negative regulation of bile acid secretion / positive regulation of neutrophil activation / negative regulation of branching involved in lung morphogenesis / positive regulation of interleukin-33 production / positive regulation of fractalkine production / positive regulation of blood microparticle formation / positive regulation of chronic inflammatory response to antigenic stimulus / response to 3,3',5-triiodo-L-thyronine ...response to Gram-negative bacterium / negative regulation of L-glutamate import across plasma membrane / negative regulation of bile acid secretion / positive regulation of neutrophil activation / negative regulation of branching involved in lung morphogenesis / positive regulation of interleukin-33 production / positive regulation of fractalkine production / positive regulation of blood microparticle formation / positive regulation of chronic inflammatory response to antigenic stimulus / response to 3,3',5-triiodo-L-thyronine / : / death receptor agonist activity / positive regulation of protein transport / positive regulation of vitamin D biosynthetic process / positive regulation of translational initiation by iron / regulation of endothelial cell apoptotic process / regulation of branching involved in salivary gland morphogenesis / chronic inflammatory response to antigenic stimulus / response to macrophage colony-stimulating factor / negative regulation of protein-containing complex disassembly / positive regulation of humoral immune response mediated by circulating immunoglobulin / positive regulation of leukocyte adhesion to arterial endothelial cell / response to gold nanoparticle / negative regulation of myelination / positive regulation of JUN kinase activity / negative regulation of vascular wound healing / negative regulation of amyloid-beta clearance / negative regulation of cytokine production involved in immune response / reactive gliosis / positive regulation of hair follicle development / positive regulation of interleukin-18 production / inflammatory response to wounding / response to resveratrol / positive regulation of action potential / epithelial cell proliferation involved in salivary gland morphogenesis / response to quercetin / TNF signaling / toll-like receptor 3 signaling pathway / vascular endothelial growth factor production / negative regulation of D-glucose import across plasma membrane / embryonic digestive tract development / positive regulation of fever generation / positive regulation of synoviocyte proliferation / positive regulation of calcineurin-NFAT signaling cascade / leukocyte tethering or rolling / necroptotic signaling pathway / negative regulation of myoblast differentiation / positive regulation of mononuclear cell migration / positive regulation of hepatocyte proliferation / response to fructose / regulation of establishment of endothelial barrier / endothelial cell apoptotic process / negative regulation of oxidative phosphorylation / response to hydrogen sulfide / positive regulation of protein-containing complex disassembly / positive regulation of protein localization to cell surface / positive regulation of osteoclast differentiation / cellular response to toxic substance / macrophage activation involved in immune response / tumor necrosis factor receptor binding / positive regulation of macrophage derived foam cell differentiation / negative regulation of mitotic cell cycle / negative regulation of systemic arterial blood pressure / positive regulation of chemokine (C-X-C motif) ligand 2 production / positive regulation of cytokine production involved in inflammatory response / positive regulation of podosome assembly / regulation of fat cell differentiation / positive regulation of heterotypic cell-cell adhesion / positive regulation of programmed cell death / positive regulation of membrane protein ectodomain proteolysis / regulation of canonical NF-kappaB signal transduction / response to L-glutamate / positive regulation of leukocyte adhesion to vascular endothelial cell / TNFR1-induced proapoptotic signaling / TNFR1-mediated ceramide production / positive regulation of extrinsic apoptotic signaling pathway / mRNA stabilization / regulation of reactive oxygen species metabolic process / negative regulation of heart rate / positive regulation of DNA biosynthetic process / positive regulation of amyloid-beta formation / positive regulation of neuroinflammatory response / negative regulation of viral genome replication / positive regulation of immunoglobulin production / negative regulation of bicellular tight junction assembly / negative regulation of fat cell differentiation / response to isolation stress / negative regulation of endothelial cell proliferation / positive regulation of MAP kinase activity / Interleukin-10 signaling / regulation of synapse organization / regulation of insulin secretion / humoral immune response / negative regulation of interleukin-6 production / histone H3K9ac reader activity / negative regulation of blood vessel endothelial cell migration / negative regulation of apoptotic signaling pathway / negative regulation of lipid storage / extrinsic apoptotic signaling pathway via death domain receptors / positive regulation of glial cell proliferation
Similarity search - Function
Tumour necrosis factor alpha / Tumour necrosis factor / Tumour necrosis factor, conserved site / Tumor necrosis factor (TNF) homology domain (THD) signature. / Tumour necrosis factor family. / TNF(Tumour Necrosis Factor) family / Jelly Rolls - #40 / Tumour necrosis factor domain / Tumor necrosis factor (TNF) homology domain (THD) profile. / Tumour necrosis factor-like domain superfamily ...Tumour necrosis factor alpha / Tumour necrosis factor / Tumour necrosis factor, conserved site / Tumor necrosis factor (TNF) homology domain (THD) signature. / Tumour necrosis factor family. / TNF(Tumour Necrosis Factor) family / Jelly Rolls - #40 / Tumour necrosis factor domain / Tumor necrosis factor (TNF) homology domain (THD) profile. / Tumour necrosis factor-like domain superfamily / Jelly Rolls / Sandwich / Mainly Beta
Similarity search - Domain/homology
Chem-A7A / Tumor necrosis factor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.55 Å
AuthorsArakaki, T.L. / Edwards, T.E. / Fairman, J.W. / Davies, D.R. / Foley, A. / Ceska, T.
CitationJournal: Nat Commun / Year: 2019
Title: Small molecules that inhibit TNF signalling by stabilising an asymmetric form of the trimer.
Authors: O'Connell, J. / Porter, J. / Kroeplien, B. / Norman, T. / Rapecki, S. / Davis, R. / McMillan, D. / Arakaki, T. / Burgin, A. / Fox Iii, D. / Ceska, T. / Lecomte, F. / Maloney, A. / Vugler, A. ...Authors: O'Connell, J. / Porter, J. / Kroeplien, B. / Norman, T. / Rapecki, S. / Davis, R. / McMillan, D. / Arakaki, T. / Burgin, A. / Fox Iii, D. / Ceska, T. / Lecomte, F. / Maloney, A. / Vugler, A. / Carrington, B. / Cossins, B.P. / Bourne, T. / Lawson, A.
History
DepositionApr 23, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 25, 2019Provider: repository / Type: Initial release
Revision 1.1Jan 1, 2020Group: 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_PubMed / _citation.title / _citation_author.name
Revision 1.2Apr 3, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.3Nov 6, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

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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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)52,7974
Polymers52,3733
Non-polymers4241
Water1,20767
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration, Runs as trimer by gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4800 Å2
ΔGint-28 kcal/mol
Surface area17810 Å2
MethodPISA
Unit cell
Length a, b, c (Å)54.170, 81.990, 94.170
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

#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
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TNF, TNFA, TNFSF2 / Production host: Escherichia coli (E. coli) / References: UniProt: P01375
#2: Chemical ChemComp-A7A / (R)-{1-[(2,5-dimethylphenyl)methyl]-6-(1-methyl-1H-pyrazol-4-yl)-1H-benzimidazol-2-yl}(pyridin-4-yl)methanol


Mass: 423.510 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C26H25N5O / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 67 / Source method: isolated from a natural source / Formula: H2O
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 Å3/Da / Density % sol: 38.8 %
Crystal growTemperature: 289 K / Method: vapor diffusion, sitting drop / pH: 8
Details: 23.2% PEG 3350, 5% MPD, 100 MM TRIS, PH 8.0, VAPOR DIFFUSION, SITTING DROP, TEMPERATURE 289K

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL7-1 / Wavelength: 1.127 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Jan 31, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.127 Å / Relative weight: 1
ReflectionResolution: 2.55→20 Å / Num. obs: 14153 / % possible obs: 99.4 % / Observed criterion σ(I): -3 / Redundancy: 6.3 % / Biso Wilson estimate: 45.53 Å2 / Rmerge(I) obs: 0.076 / Net I/σ(I): 18.54
Reflection shellResolution: 2.55→2.62 Å / Redundancy: 6.4 % / Rmerge(I) obs: 0.522 / Mean I/σ(I) obs: 3.8 / Num. unique obs: 1382 / % possible all: 100

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Processing

Software
NameVersionClassification
XDSdata reduction
XSCALEdata scaling
REFMAC5.6.0117refinement
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: unpublished structure

Resolution: 2.55→19.89 Å / Cor.coef. Fo:Fc: 0.949 / Cor.coef. Fo:Fc free: 0.91 / SU B: 10.143 / SU ML: 0.22 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 1.025 / ESU R Free: 0.309 / Details: HYDROGENS HAVE BEEN ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.244 721 5.1 %RANDOM
Rwork0.185 ---
obs0.188 14153 99.4 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 29.31 Å2
Baniso -1Baniso -2Baniso -3
1-1.37 Å20 Å20 Å2
2---1.6 Å20 Å2
3---0.23 Å2
Refinement stepCycle: LAST / Resolution: 2.55→19.89 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3083 0 32 67 3182
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0140.023187
X-RAY DIFFRACTIONr_bond_other_d0.0010.022044
X-RAY DIFFRACTIONr_angle_refined_deg1.4161.9714357
X-RAY DIFFRACTIONr_angle_other_deg0.8232.9964995
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.5665396
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.57124.538130
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.58815464
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.5731513
X-RAY DIFFRACTIONr_chiral_restr0.0840.2501
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.0213538
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02616
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.55→2.62 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.474 44 -
Rwork0.287 870 -
obs--99.78 %

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