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- PDB-8z8m: Crystal structure of human TNF alpha in complex with TNF30(VHH) d... -

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Basic information

Entry
Database: PDB / ID: 8z8m
TitleCrystal structure of human TNF alpha in complex with TNF30(VHH) domain of ozoralizumab
Components
  • TNF30:VHH
  • Tumor necrosis factor
KeywordsCYTOKINE / TNF / VHH / Ozoralizumab
Function / homology
Function and homology information


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 / negative regulation of signaling receptor activity / positive regulation of chronic inflammatory response to antigenic stimulus / positive regulation of fractalkine production ...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 / negative regulation of signaling receptor activity / positive regulation of chronic inflammatory response to antigenic stimulus / positive regulation of fractalkine production / positive regulation of leukocyte adhesion to arterial endothelial cell / positive regulation of vitamin D biosynthetic process / positive regulation of translational initiation by iron / response to macrophage colony-stimulating factor / regulation of membrane lipid metabolic process / regulation of endothelial cell apoptotic process / chronic inflammatory response to antigenic stimulus / regulation of branching involved in salivary gland morphogenesis / negative regulation of protein-containing complex disassembly / response to 3,3',5-triiodo-L-thyronine / 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 bicellular tight junction assembly / negative regulation of cytokine production involved in immune response / negative regulation of vascular wound healing / : / negative regulation of amyloid-beta clearance / response to isolation stress / positive regulation of action potential / inflammatory response to wounding / positive regulation of interleukin-18 production / death receptor agonist activity / positive regulation of protein transport / TNF signaling / epithelial cell proliferation involved in salivary gland morphogenesis / toll-like receptor 3 signaling pathway / embryonic digestive tract development / vascular endothelial growth factor production / leukocyte migration involved in inflammatory response / necroptotic signaling pathway / response to fructose / positive regulation of neuroinflammatory response / positive regulation of synoviocyte proliferation / positive regulation of calcineurin-NFAT signaling cascade / leukocyte tethering or rolling / positive regulation of mononuclear cell migration / positive regulation of fever generation / negative regulation of myoblast differentiation / cellular response to toxic substance / regulation of establishment of endothelial barrier / endothelial cell apoptotic process / negative regulation of D-glucose import / negative regulation of oxidative phosphorylation / positive regulation of protein localization to cell surface / macrophage activation involved in immune response / positive regulation of osteoclast differentiation / tumor necrosis factor receptor binding / positive regulation of protein-containing complex disassembly / negative regulation of systemic arterial blood pressure / positive regulation of heterotypic cell-cell adhesion / positive regulation of cytokine production involved in inflammatory response / positive regulation of macrophage derived foam cell differentiation / regulation of immunoglobulin production / TNFR1-mediated ceramide production / positive regulation of programmed cell death / positive regulation of hepatocyte proliferation / positive regulation of membrane protein ectodomain proteolysis / positive regulation of chemokine (C-X-C motif) ligand 2 production / positive regulation of extrinsic apoptotic signaling pathway / positive regulation of podosome assembly / regulation of canonical NF-kappaB signal transduction / regulation of fat cell differentiation / TNFR1-induced proapoptotic signaling / positive regulation of leukocyte adhesion to vascular endothelial cell / regulation of metabolic process / regulation of reactive oxygen species metabolic process / negative regulation of heart rate / positive regulation of amyloid-beta formation / positive regulation of DNA biosynthetic process / negative regulation of viral genome replication / response to L-glutamate / negative regulation of fat cell differentiation / regulation of synapse organization / Interleukin-10 signaling / negative regulation of endothelial cell proliferation / negative regulation of interleukin-6 production / negative regulation of blood vessel endothelial cell migration / humoral immune response / negative regulation of apoptotic signaling pathway / negative regulation of lipid storage / negative regulation of mitotic cell cycle / extrinsic apoptotic signaling pathway via death domain receptors / positive regulation of JUN kinase activity / negative regulation of extrinsic apoptotic signaling pathway in absence of ligand / cell surface receptor signaling pathway via JAK-STAT / phagocytic cup / negative regulation of osteoblast differentiation / positive regulation of synaptic transmission
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 / Tumour necrosis factor domain / Tumor necrosis factor (TNF) homology domain (THD) profile. / Tumour necrosis factor-like domain superfamily
Similarity search - Domain/homology
Tumor necrosis factor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.59 Å
AuthorsMima, M. / Mishima-Tsumagari, C.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Biochem.Biophys.Res.Commun. / Year: 2024
Title: Structural design of the anti-TNF alpha therapeutic NANOBODY® compound, ozoralizumab, to support its potent and sustained clinical efficacy.
Authors: Mima, M. / Mishima-Tsumagari, C. / Nakano, K. / Morimoto, M. / Ogata, H. / Sakata, M. / Iwaoka, R. / Iwata, K. / Hachiuma, K. / Iwamoto, K. / Fujii, Y. / Kurokawa, T.
History
DepositionApr 22, 2024Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Sep 4, 2024Provider: repository / Type: Initial release
Revision 1.1Oct 30, 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: TNF30:VHH
C: Tumor necrosis factor
D: TNF30:VHH
E: Tumor necrosis factor
F: TNF30:VHH
G: Tumor necrosis factor
H: TNF30:VHH
I: Tumor necrosis factor
J: TNF30:VHH
K: Tumor necrosis factor
L: TNF30:VHH


Theoretical massNumber of molelcules
Total (without water)186,57012
Polymers186,57012
Non-polymers00
Water82946
1
A: Tumor necrosis factor
B: TNF30:VHH
C: Tumor necrosis factor
D: TNF30:VHH
E: Tumor necrosis factor
F: TNF30:VHH


Theoretical massNumber of molelcules
Total (without water)93,2856
Polymers93,2856
Non-polymers00
Water1086
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
G: Tumor necrosis factor
H: TNF30:VHH
I: Tumor necrosis factor
J: TNF30:VHH
K: Tumor necrosis factor
L: TNF30:VHH


Theoretical massNumber of molelcules
Total (without water)93,2856
Polymers93,2856
Non-polymers00
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)56.030, 121.160, 123.610
Angle α, β, γ (deg.)90.00, 94.58, 90.00
Int Tables number4
Space group name H-MP1211

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Components

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


Mass: 17370.658 Da / Num. of mol.: 6 / Fragment: UNP residues 76-232
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: Antibody
TNF30:VHH


Mass: 13724.277 Da / Num. of mol.: 6
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human) / Strain (production host): ExpiCHO-S
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 46 / 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: 2.44 Å3/Da / Density % sol: 49.53 %
Crystal growTemperature: 293 K / Method: vapor diffusion / pH: 6.5
Details: 0.03M Diethylene glycol; 0.03M Triethylene glycol; 0.03M Tetraethylene glycol; 0.03M Pentaethylene glycol 0.05M Sodium HEPES; 0.05M MOPS pH7.5 12.5% v/v MPD; 12.5% PEG 1000; 12.5% w/v PEG 3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SPring-8 / Beamline: BL32XU / Wavelength: 1 Å
DetectorType: DECTRIS EIGER X 9M / Detector: PIXEL / Date: Jul 29, 2023
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.59→45.79 Å / Num. obs: 50898 / % possible obs: 99.3 % / Redundancy: 4.2 % / CC1/2: 0.991 / Net I/σ(I): 7.32
Reflection shellResolution: 2.59→2.75 Å / Num. unique obs: 8380 / CC1/2: 0.531

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Processing

Software
NameVersionClassification
REFMAC5.8.0267refinement
XDSdata reduction
XDSdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.59→45.79 Å / Cor.coef. Fo:Fc: 0.949 / Cor.coef. Fo:Fc free: 0.913 / SU B: 21.263 / SU ML: 0.405 / Cross valid method: THROUGHOUT / ESU R Free: 0.355 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.26876 2381 4.7 %RANDOM
Rwork0.20851 ---
obs0.2112 48495 99.31 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 76.882 Å2
Baniso -1Baniso -2Baniso -3
1--0.98 Å20 Å2-1.74 Å2
2--4.21 Å2-0 Å2
3----2.91 Å2
Refinement stepCycle: 1 / Resolution: 2.59→45.79 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms12084 0 0 46 12130
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.01312374
X-RAY DIFFRACTIONr_bond_other_d0.0010.01511646
X-RAY DIFFRACTIONr_angle_refined_deg1.4721.63916816
X-RAY DIFFRACTIONr_angle_other_deg1.1661.57626736
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.37251538
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.01322.135637
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.268151992
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.6341581
X-RAY DIFFRACTIONr_chiral_restr0.0540.21555
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0214162
X-RAY DIFFRACTIONr_gen_planes_other0.0010.022972
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_it6.8198.016203
X-RAY DIFFRACTIONr_mcbond_other6.8188.016202
X-RAY DIFFRACTIONr_mcangle_it10.71711.9927724
X-RAY DIFFRACTIONr_mcangle_other10.71711.9937725
X-RAY DIFFRACTIONr_scbond_it6.3548.3926171
X-RAY DIFFRACTIONr_scbond_other6.3538.3926172
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other10.00212.3859093
X-RAY DIFFRACTIONr_long_range_B_refined17.18248792
X-RAY DIFFRACTIONr_long_range_B_other17.18248791
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.59→2.657 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.354 192 -
Rwork0.347 3566 -
obs--99.58 %

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