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- PDB-3l9j: Selection of a novel highly specific TNFalpha antagonist: Insight... -

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Basic information

Entry
Database: PDB / ID: 3l9j
TitleSelection of a novel highly specific TNFalpha antagonist: Insight from the crystal structure of the antagonist-TNFalpha complex
Components
  • TNFalpha
  • Tumor necrosis factor, soluble form
KeywordsIMMUNE SYSTEM / TNF-alpha / antagonist / in vitro selection / Cell membrane / Cytokine / Disulfide bond / Glycoprotein / Lipoprotein / Secreted / Signal-anchor / Transmembrane
Function / homology
Function and homology information


kringle domain binding / platelet dense granule lumen / granular component / negative regulation of L-glutamate import across plasma membrane / negative regulation of branching involved in lung morphogenesis / negative regulation of bile acid secretion / response to Gram-negative bacterium / positive regulation of interleukin-33 production / positive regulation of neutrophil activation / positive regulation of blood microparticle formation ...kringle domain binding / platelet dense granule lumen / granular component / negative regulation of L-glutamate import across plasma membrane / negative regulation of branching involved in lung morphogenesis / negative regulation of bile acid secretion / response to Gram-negative bacterium / positive regulation of interleukin-33 production / positive regulation of neutrophil activation / positive regulation of blood microparticle formation / positive regulation of chronic inflammatory response to antigenic stimulus / positive regulation of fractalkine production / positive regulation of translational initiation by iron / : / response to macrophage colony-stimulating factor / positive regulation of leukocyte adhesion to arterial endothelial cell / positive regulation of vitamin D biosynthetic process / response to 3,3',5-triiodo-L-thyronine / regulation of membrane lipid metabolic process / regulation of endothelial cell apoptotic process / regulation of branching involved in salivary gland morphogenesis / chronic inflammatory response to antigenic stimulus / negative regulation of protein-containing complex disassembly / positive regulation of humoral immune response mediated by circulating immunoglobulin / response to gold nanoparticle / negative regulation of myosin-light-chain-phosphatase activity / positive regulation of hair follicle development / positive regulation of plasminogen activation / negative regulation of myelination / negative regulation of amyloid-beta clearance / negative regulation of cytokine production involved in immune response / negative regulation of vascular wound healing / negative regulation of bicellular tight junction assembly / response to isolation stress / death receptor agonist activity / cellular response to toxic substance / inflammatory response to wounding / positive regulation of calcidiol 1-monooxygenase activity / positive regulation of I-kappaB phosphorylation / TNF signaling / sequestering of triglyceride / positive regulation of action potential / positive regulation of protein transport / positive regulation of interleukin-18 production / epithelial cell proliferation involved in salivary gland morphogenesis / toll-like receptor 3 signaling pathway / leukocyte migration involved in inflammatory response / embryonic digestive tract development / positive regulation of superoxide dismutase activity / necroptotic signaling pathway / vascular endothelial growth factor production / positive regulation of calcineurin-NFAT signaling cascade / positive regulation of neuroinflammatory response / response to fructose / leukocyte tethering or rolling / positive regulation of synoviocyte proliferation / positive regulation of mononuclear cell migration / positive regulation of fever generation / negative regulation of myoblast differentiation / positive regulation of protein localization to cell surface / TNFR1-mediated ceramide production / macrophage activation involved in immune response / negative regulation of glucose import / regulation of establishment of endothelial barrier / endothelial cell apoptotic process / positive regulation of membrane protein ectodomain proteolysis / negative regulation of oxidative phosphorylation / negative regulation of systemic arterial blood pressure / positive regulation of cytokine production involved in inflammatory response / positive regulation of osteoclast differentiation / tumor necrosis factor receptor binding / positive regulation of chemokine (C-X-C motif) ligand 2 production / regulation of immunoglobulin production / positive regulation of hepatocyte proliferation / positive regulation of protein-containing complex disassembly / positive regulation of extrinsic apoptotic signaling pathway / positive regulation of programmed cell death / positive regulation of podosome assembly / regulation of canonical NF-kappaB signal transduction / regulation of reactive oxygen species metabolic process / TNFR1-induced proapoptotic signaling / positive regulation of heterotypic cell-cell adhesion / regulation of fat cell differentiation / response to L-glutamate / positive regulation of leukocyte adhesion to vascular endothelial cell / negative regulation of heart rate / cortical actin cytoskeleton organization / negative regulation of fat cell differentiation / phagocytic cup / positive regulation of DNA biosynthetic process / cellular response to organic substance / regulation of synapse organization / positive regulation of amyloid-beta formation / negative regulation of viral genome replication / negative regulation of endothelial cell proliferation / bone mineralization / negative regulation of blood vessel endothelial cell migration / Interleukin-10 signaling / antiviral innate immune response / negative regulation of interleukin-6 production
Similarity search - Function
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 / Jelly Rolls - #40 / Tumour necrosis factor-like domain superfamily ...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 / Jelly Rolls - #40 / Tumour necrosis factor-like domain superfamily / C-type lectin, conserved site / C-type lectin domain signature. / Mannose-Binding Protein A; Chain A / Mannose-Binding Protein A, subunit A / Lectin C-type domain / C-type lectin domain profile. / C-type lectin-like / C-type lectin (CTL) or carbohydrate-recognition domain (CRD) / C-type lectin-like/link domain superfamily / C-type lectin fold / Jelly Rolls / Roll / Sandwich / Mainly Beta / Alpha Beta
Similarity search - Domain/homology
Tumor necrosis factor / Tetranectin
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.1 Å
AuthorsByla, P. / Andersen, M.H. / Thogersen, H.C. / Gad, H.H. / Hartmann, R.
CitationJournal: J.Biol.Chem. / Year: 2010
Title: Selection of a novel and highly specific TNF{alpha} antagonist: insight from the crystal structure of the antagonist-TNF{alpha} complex
Authors: Byla, P. / Andersen, M.H. / Holtet, T.L. / Jacobsen, H. / Munch, M. / Gad, H.H. / Thogersen, H.C. / Hartmann, R.
History
DepositionJan 5, 2010Deposition site: RCSB / Processing site: PDBJ
Revision 1.0Feb 23, 2010Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Feb 26, 2014Group: Derived calculations
Revision 1.3Jan 31, 2018Group: Data collection / Experimental preparation / Category: diffrn_source / exptl_crystal_grow
Item: _diffrn_source.pdbx_synchrotron_site / _exptl_crystal_grow.pdbx_details / _exptl_crystal_grow.temp
Revision 1.4Nov 1, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / diffrn_source / pdbx_initial_refinement_model / pdbx_struct_conn_angle / struct_conn / struct_ref_seq / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _diffrn_source.pdbx_synchrotron_site / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_ref_seq.db_align_end / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
C: TNFalpha
T: Tumor necrosis factor, soluble form
hetero molecules


Theoretical massNumber of molelcules
Total (without water)31,8363
Polymers31,8122
Non-polymers241
Water4,432246
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)83.905, 83.905, 149.172
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number182
Space group name H-MP6322
Components on special symmetry positions
IDModelComponents
11T-200-

HOH

21T-283-

HOH

31T-284-

HOH

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Components

#1: Protein TNFalpha


Mass: 15314.166 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Plasmid: pT7CIIH6 / Production host: Escherichia coli (E. coli) / References: UniProt: P05452*PLUS
#2: Protein Tumor necrosis factor, soluble form / / TNF-alpha / Tumor necrosis factor ligand superfamily member 2 / TNF-a / Cachectin


Mass: 16497.684 Da / Num. of mol.: 1 / Fragment: UNP residues 85-233
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Plasmid: pT7CIIH6 / Production host: Escherichia coli (E. coli) / References: UniProt: P01375
#3: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 246 / Source method: isolated from a natural source / Formula: H2O
Sequence detailsTHE NUMBER 52 IS SIMPLY SKIPPED IN CHAIN C.

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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: 2.38 Å3/Da / Density % sol: 48.37 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 8
Details: 0.1M Tris, 0.35M MgAc, 20% 2-propanol, pH 8.0, VAPOR DIFFUSION, SITTING DROP, temperature 293K

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Data collection

Diffraction
IDMean temperature (K)Crystal-ID
11001
21001
Diffraction source
SourceSiteBeamlineIDWavelength (Å)
SYNCHROTRONEMBL/DESY, HAMBURG X1210.815
SYNCHROTRONMAX II I911-321
Detector
TypeIDDetector
MARRESEARCH1CCD
MARRESEARCH2CCD
Radiation
IDProtocolMonochromatic (M) / Laue (L)Scattering typeWavelength-ID
1SINGLE WAVELENGTHMx-ray1
2SINGLE WAVELENGTHMx-ray1
Radiation wavelength
IDWavelength (Å)Relative weight
10.8151
211
ReflectionResolution: 2.1→74 Å / Num. all: 17880 / Num. obs: 17855 / % possible obs: 99.86 % / Observed criterion σ(F): 3 / Observed criterion σ(I): 3

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Processing

Software
NameVersionClassificationNB
REFMAC5.2.0019refinement
PDB_EXTRACT3.005data extraction
MAR345dtbdata collection
HKL-2000data reduction
HKL-2000data scaling
PHASESphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1TNF for chain T and 1TN3 for chain C; For 1TN3 the randomized loops was removed from teh search model. These loop is 116-122 (loop 1) and 145-150 (loop 4)

1tnf

1tn3

1tn3


Resolution: 2.1→41.95 Å / Cor.coef. Fo:Fc: 0.958 / Cor.coef. Fo:Fc free: 0.947 / Occupancy max: 1 / Occupancy min: 0.33 / SU B: 3.821 / SU ML: 0.104 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.205 / ESU R Free: 0.172 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.217 968 5.1 %RANDOM
Rwork0.173 ---
obs0.175 17855 99.86 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 73.34 Å2 / Biso mean: 29.367 Å2 / Biso min: 12.25 Å2
Baniso -1Baniso -2Baniso -3
1-0.29 Å20.15 Å20 Å2
2--0.29 Å20 Å2
3----0.44 Å2
Refinement stepCycle: LAST / Resolution: 2.1→41.95 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2206 0 1 246 2453
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0160.0222267
X-RAY DIFFRACTIONr_angle_refined_deg1.4751.943082
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.425276
X-RAY DIFFRACTIONr_dihedral_angle_2_deg38.43124.182110
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.12615365
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.2221514
X-RAY DIFFRACTIONr_chiral_restr0.110.2328
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.021756
X-RAY DIFFRACTIONr_nbd_refined0.2070.2928
X-RAY DIFFRACTIONr_nbtor_refined0.3060.21543
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1910.2203
X-RAY DIFFRACTIONr_metal_ion_refined0.0450.22
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.2340.262
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.3190.238
X-RAY DIFFRACTIONr_mcbond_it1.1291.51417
X-RAY DIFFRACTIONr_mcangle_it1.97722224
X-RAY DIFFRACTIONr_scbond_it2.9153987
X-RAY DIFFRACTIONr_scangle_it4.7184.5858
LS refinement shellResolution: 2.1→2.154 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.276 82 -
Rwork0.173 1261 -
all-1343 -
obs--99.85 %

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