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- PDB-7kp8: asymmetric mTNF-alpha hTNFR1 complex -

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Basic information

Entry
Database: PDB / ID: 7kp8
Titleasymmetric mTNF-alpha hTNFR1 complex
Components
  • Tumor necrosis factor receptor superfamily member 1ACD120
  • Tumor necrosis factor
KeywordsCYTOKINE / Tumour necrosis factor alpha / TNF / Receptor / TNFR1 / asymmetric / protein-protein inhibitor
Function / homology
Function and homology information


TNF signaling / negative regulation of alkaline phosphatase activity / TNFR1-mediated ceramide production / TNFR1-induced proapoptotic signaling / positive regulation of amide metabolic process / cellular extravasation / tumor necrosis factor receptor superfamily complex / pulmonary valve development / TNFR1-induced NF-kappa-B signaling pathway / negative regulation of L-glutamate import across plasma membrane ...TNF signaling / negative regulation of alkaline phosphatase activity / TNFR1-mediated ceramide production / TNFR1-induced proapoptotic signaling / positive regulation of amide metabolic process / cellular extravasation / tumor necrosis factor receptor superfamily complex / pulmonary valve development / TNFR1-induced NF-kappa-B signaling pathway / 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 / negative regulation of branching involved in lung morphogenesis / positive regulation of interleukin-33 production / positive regulation of blood microparticle formation / Regulation of TNFR1 signaling / positive regulation of chronic inflammatory response to antigenic stimulus / positive regulation of fractalkine production / : / response to macrophage colony-stimulating factor / aortic valve development / tumor necrosis factor receptor activity / positive regulation of lipid metabolic process / positive regulation of leukocyte adhesion to arterial endothelial cell / positive regulation of vitamin D biosynthetic process / negative regulation of extracellular matrix constituent secretion / positive regulation of translational initiation by iron / response to 3,3',5-triiodo-L-thyronine / positive regulation of apoptotic process involved in morphogenesis / regulation of membrane lipid metabolic process / regulation of endothelial cell apoptotic process / TNFR2 non-canonical NF-kB pathway / regulation of branching involved in salivary gland morphogenesis / chronic inflammatory response to antigenic stimulus / negative regulation of protein-containing complex disassembly / response to gold nanoparticle / positive regulation of humoral immune response mediated by circulating immunoglobulin / positive regulation of hair follicle development / negative regulation of myelination / negative regulation of amyloid-beta clearance / TNFs bind their physiological receptors / negative regulation of vascular wound healing / negative regulation of bicellular tight junction assembly / response to isolation stress / negative regulation of cardiac muscle hypertrophy / death receptor agonist activity / tumor necrosis factor binding / negative regulation of cytokine production involved in immune response / inflammatory response to wounding / cellular response to toxic substance / positive regulation of I-kappaB phosphorylation / positive regulation of action potential / sequestering of triglyceride / positive regulation of protein transport / TNF signaling / positive regulation of interleukin-18 production / epithelial cell proliferation involved in salivary gland morphogenesis / regulation of osteoclast differentiation / toll-like receptor 3 signaling pathway / leukocyte migration involved in inflammatory response / embryonic digestive tract development / necroptotic signaling pathway / vascular endothelial growth factor production / positive regulation of calcineurin-NFAT signaling cascade / response to fructose / leukocyte tethering or rolling / positive regulation of synoviocyte proliferation / positive regulation of fever generation / negative regulation of myoblast differentiation / positive regulation of protein localization to cell surface / TNFR1-mediated ceramide production / negative regulation of glucose import / endothelial cell apoptotic process / regulation of establishment of endothelial barrier / macrophage activation involved in immune response / regulation of tumor necrosis factor-mediated signaling pathway / negative regulation of oxidative phosphorylation / positive regulation of cytokine production involved in inflammatory response / positive regulation of osteoclast differentiation / tumor necrosis factor receptor binding / negative regulation of systemic arterial blood pressure / positive regulation of chemokine (C-X-C motif) ligand 2 production / positive regulation of protein-containing complex disassembly / positive regulation of hepatocyte proliferation / regulation of immunoglobulin production / positive regulation of programmed cell death / positive regulation of extrinsic apoptotic signaling pathway / positive regulation of podosome assembly / regulation of canonical NF-kappaB signal transduction / positive regulation of membrane protein ectodomain proteolysis / regulation of reactive oxygen species metabolic process / TNFR1-induced proapoptotic signaling / positive regulation of heterotypic cell-cell adhesion / positive regulation of leukocyte adhesion to vascular endothelial cell / cortical actin cytoskeleton organization / response to L-glutamate / positive regulation of DNA biosynthetic process / negative regulation of fat cell differentiation / phagocytic cup
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 / TNF family signature. / Tumour necrosis factor family. / TNF family profile. / TNF(Tumour Necrosis Factor) family ...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 / TNF family signature. / Tumour necrosis factor family. / TNF family profile. / TNF(Tumour Necrosis Factor) family / Tumour necrosis factor domain / TNFR/NGFR family cysteine-rich region domain profile. / TNFR/NGFR cysteine-rich region / TNFR/NGFR family cysteine-rich region signature. / Tumor necrosis factor receptor / nerve growth factor receptor repeats. / TNFR/NGFR cysteine-rich region / 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
Similarity search - Domain/homology
Chem-A7G / Tumor necrosis factor / Tumor necrosis factor receptor superfamily member 1A
Similarity search - Component
Biological speciesMus musculus (house mouse)
Homo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.15 Å
AuthorsArakaki, T.L. / Fox III, D. / Edwards, T.E. / Foley, A. / Ceska, T.
CitationJournal: Nat Commun / Year: 2021
Title: Structural insights into the disruption of TNF-TNFR1 signalling by small molecules stabilising a distorted TNF.
Authors: McMillan, D. / Martinez-Fleites, C. / Porter, J. / Fox 3rd, D. / Davis, R. / Mori, P. / Ceska, T. / Carrington, B. / Lawson, A. / Bourne, T. / O'Connell, J.
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 / _citation_author.identifier_ORCID / _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

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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
E: Tumor necrosis factor receptor superfamily member 1A
F: Tumor necrosis factor receptor superfamily member 1A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)81,5276
Polymers81,0785
Non-polymers4491
Water724
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area9330 Å2
ΔGint-41 kcal/mol
Surface area28890 Å2
MethodPISA
Unit cell
Length a, b, c (Å)133.577, 133.577, 141.445
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number92
Space group name H-MP41212

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Components

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


Mass: 16324.518 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Gene: Tnf, Tnfa, Tnfsf2 / Production host: Escherichia coli (E. coli) / References: UniProt: P06804
#2: Protein Tumor necrosis factor receptor superfamily member 1A / CD120 / Tumor necrosis factor receptor 1 / TNF-R1 / Tumor necrosis factor receptor type I / TNFR-I / p55 / p60


Mass: 16052.028 Da / Num. of mol.: 2 / Mutation: N25E, C153S
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TNFRSF1A, TNFAR, TNFR1 / Production host: unidentified baculovirus / References: UniProt: P19438
#3: Chemical ChemComp-A7G / 1-{[2-(difluoromethoxy)phenyl]methyl}-2-methyl-6-[6-(piperazin-1-yl)pyridin-3-yl]-1H-benzimidazole


Mass: 449.496 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H25F2N5O / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 4 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 3.89 Å3/Da / Density % sol: 68.39 %
Crystal growTemperature: 298 K / Method: vapor diffusion / pH: 7.65
Details: 800 mM sodium potassium tartrate, 0.45% PEG 5000 MME, 100 mM Tris, pH7.65. Vapor diffusion, sitting drop, temperature 289K

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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 225 mm CCD / Detector: CCD / Date: Aug 17, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9787 Å / Relative weight: 1
ReflectionResolution: 3.15→50 Å / Num. obs: 22757 / % possible obs: 99.9 % / Redundancy: 4.9 % / Rmerge(I) obs: 0.19 / Rpim(I) all: 0.095 / Rrim(I) all: 0.212 / Rsym value: 0.188 / Net I/av σ(I): 3.529 / Net I/σ(I): 8.3
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. unique obsRpim(I) allRrim(I) allRsym value% possible all
3.15-3.3250.8960.832490.451.0070.896100
3.32-3.5250.5711.330940.2860.6420.571100
3.52-3.7650.3662.128950.1820.410.366100
3.76-4.074.90.2453.127270.1240.2760.245100
4.07-4.454.90.1564.925200.0780.1750.156100
4.45-4.984.90.126.322960.060.1350.12100
4.98-5.754.80.1236.120290.0610.1380.123100
5.75-7.044.80.1146.617580.0580.1280.114100
7.04-9.964.60.06111.913790.0310.0690.06199.9
9.96-48.5584.20.0455.28100.0270.0530.04597.8

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Processing

Software
NameVersionClassification
XDSdata reduction
SCALAdata scaling
REFMAC5.7.0029refinement
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: unpublished structure

Resolution: 3.15→48.61 Å / Cor.coef. Fo:Fc: 0.899 / Cor.coef. Fo:Fc free: 0.867 / SU B: 17.12 / SU ML: 0.303 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 1.18 / ESU R Free: 0.417 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES: REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2716 1152 5.1 %RANDOM
Rwork0.2216 21552 --
obs0.2241 22704 99.85 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 137.12 Å2 / Biso mean: 67.3777 Å2 / Biso min: 33.98 Å2
Baniso -1Baniso -2Baniso -3
1-1.78 Å20 Å20 Å2
2--1.78 Å2-0 Å2
3----3.57 Å2
Refinement stepCycle: LAST / Resolution: 3.15→48.61 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4903 0 33 4 4940
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.0195070
X-RAY DIFFRACTIONr_bond_other_d0.0050.024390
X-RAY DIFFRACTIONr_angle_refined_deg1.2221.9436947
X-RAY DIFFRACTIONr_angle_other_deg0.9373.0039948
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.3055663
X-RAY DIFFRACTIONr_dihedral_angle_2_deg38.09224.811212
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.1215652
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.6051513
X-RAY DIFFRACTIONr_chiral_restr0.0680.2779
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0215979
X-RAY DIFFRACTIONr_gen_planes_other0.0040.021194
LS refinement shellResolution: 3.15→3.232 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.366 88 -
Rwork0.309 1539 -
all-1627 -
obs--100 %

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