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- PDB-9ojo: Crystal structure of TNF alpha in complex with compound 1 -

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Basic information

Entry
Database: PDB / ID: 9ojo
TitleCrystal structure of TNF alpha in complex with compound 1
ComponentsTumor necrosis factor
KeywordsCYTOKINE / Tumor necrosis factor alpha / structure-based drug design
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 / positive regulation of chronic inflammatory response to antigenic stimulus / positive regulation of fractalkine production / positive regulation of leukocyte adhesion to arterial endothelial cell ...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 leukocyte adhesion to arterial endothelial cell / positive regulation of vitamin D biosynthetic process / positive regulation of protein transport / 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 / response to isolation stress / negative regulation of cytokine production involved in immune response / negative regulation of vascular wound healing / negative regulation of amyloid-beta clearance / inflammatory response to wounding / positive regulation of interleukin-18 production / death receptor agonist activity / positive regulation of action potential / TNF signaling / epithelial cell proliferation involved in salivary gland morphogenesis / embryonic digestive tract development / toll-like receptor 3 signaling pathway / negative regulation of D-glucose import / vascular endothelial growth factor production / leukocyte migration involved in inflammatory response / response to fructose / positive regulation of neuroinflammatory response / positive regulation of synoviocyte proliferation / necroptotic signaling pathway / 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 / positive regulation of protein-containing complex disassembly / regulation of establishment of endothelial barrier / endothelial cell apoptotic process / negative regulation of oxidative phosphorylation / cellular response to toxic substance / positive regulation of protein localization to cell surface / positive regulation of osteoclast differentiation / macrophage activation involved in immune response / negative regulation of systemic arterial blood pressure / tumor necrosis factor receptor binding / 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 hepatocyte proliferation / positive regulation of programmed cell death / positive regulation of membrane protein ectodomain proteolysis / positive regulation of chemokine (C-X-C motif) ligand 2 production / positive regulation of podosome assembly / positive regulation of extrinsic apoptotic signaling pathway / regulation of canonical NF-kappaB signal transduction / regulation of fat cell differentiation / positive regulation of leukocyte adhesion to vascular endothelial cell / TNFR1-induced proapoptotic signaling / regulation of metabolic process / negative regulation of bicellular tight junction assembly / regulation of reactive oxygen species metabolic process / positive regulation of DNA biosynthetic process / response to L-glutamate / positive regulation of amyloid-beta formation / negative regulation of heart rate / negative regulation of viral genome replication / regulation of synapse organization / negative regulation of fat cell differentiation / negative regulation of endothelial cell proliferation / Interleukin-10 signaling / positive regulation of JUN kinase activity / 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 / negative regulation of osteoblast differentiation / cell surface receptor signaling pathway via JAK-STAT / negative regulation of extrinsic apoptotic signaling pathway in absence of ligand / positive regulation of synaptic transmission / skeletal muscle contraction / positive regulation of MAP kinase activity / detection of mechanical stimulus involved in sensory perception of pain
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: 1.358 Å
AuthorsJudge, R.A. / Bian, Z. / Longenecker, K.L.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J.Med.Chem. / Year: 2025
Title: Discovery of Orally Efficacious Bridged Piperazines as smTNF Modulators.
Authors: Bian, Z. / Schmidt, R.G. / Wilson, N.S. / Duignan, D.B. / Breinlinger, E. / Dombrowski, A.W. / Erdman, P. / Foley, C.M. / Friedman, M. / Gfesser, G.A. / Goess, C.A. / Gomtsyan, A. / Judge, R. ...Authors: Bian, Z. / Schmidt, R.G. / Wilson, N.S. / Duignan, D.B. / Breinlinger, E. / Dombrowski, A.W. / Erdman, P. / Foley, C.M. / Friedman, M. / Gfesser, G.A. / Goess, C.A. / Gomtsyan, A. / Judge, R.A. / Kikuchi, R. / Koshman, Y. / Liu, X. / Longenecker, K.L. / McClure, A. / Sippy, K. / Wetter, J.M. / Stoffel, R. / Vasudevan, A.
History
DepositionMay 8, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 23, 2025Provider: repository / Type: Initial release

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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)52,8904
Polymers52,5063
Non-polymers3841
Water6,107339
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5550 Å2
ΔGint-30 kcal/mol
Surface area17360 Å2
MethodPISA
Unit cell
Length a, b, c (Å)52.669, 80.173, 92.248
Angle α, β, γ (deg.)90, 90, 90
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: 17501.854 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-A1CB1 / 2-{5-[(1S,10S)-1-phenyl-1,2,3,4-tetrahydropyrido[1,2-a][1,3]benzimidazol-8-yl]pyrimidin-2-yl}propan-2-ol


Mass: 384.474 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H24N4O / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 339 / Source method: isolated from a natural source / Formula: H2O
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: 1.85 Å3/Da / Density % sol: 33.68 %
Crystal growTemperature: 296 K / Method: vapor diffusion / pH: 8.5 / Details: 30% (w/v) PEG 1000, 0.1M Tris pH 8.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jul 24, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.358→60.513 Å / Num. obs: 83658 / % possible obs: 98.6 % / Redundancy: 6.7 % / CC1/2: 0.999 / Net I/σ(I): 11.3
Reflection shellResolution: 1.358→1.382 Å / Num. unique obs: 4059 / CC1/2: 0.335

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Processing

Software
NameVersionClassification
BUSTER2.11.7refinement
autoPROCdata reduction
autoPROCdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.358→60.51 Å / Cor.coef. Fo:Fc: 0.957 / Cor.coef. Fo:Fc free: 0.957 / SU R Cruickshank DPI: 0.062 / Cross valid method: THROUGHOUT / SU R Blow DPI: 0.064 / SU Rfree Blow DPI: 0.063 / SU Rfree Cruickshank DPI: 0.061
RfactorNum. reflection% reflectionSelection details
Rfree0.2171 4078 -RANDOM
Rwork0.2 ---
obs0.2008 83344 98.2 %-
Displacement parametersBiso mean: 26.95 Å2
Baniso -1Baniso -2Baniso -3
1--3.0555 Å20 Å20 Å2
2--1.1153 Å20 Å2
3---1.9402 Å2
Refine analyzeLuzzati coordinate error obs: 0.21 Å
Refinement stepCycle: LAST / Resolution: 1.358→60.51 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3171 0 29 339 3539
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0083276HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.034464HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1070SINUSOIDAL2
X-RAY DIFFRACTIONt_gen_planes553HARMONIC5
X-RAY DIFFRACTIONt_it3276HARMONIC10
X-RAY DIFFRACTIONt_chiral_improper_torsion418SEMIHARMONIC5
X-RAY DIFFRACTIONt_ideal_dist_contact3015SEMIHARMONIC4
X-RAY DIFFRACTIONt_omega_torsion4.36
X-RAY DIFFRACTIONt_other_torsion14.69
LS refinement shellResolution: 1.36→1.37 Å
RfactorNum. reflection% reflection
Rfree0.2911 77 -
Rwork0.2575 --
obs0.2591 1667 89.66 %
Refinement TLS params.

Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
10.7418-0.1218-0.18270.75850.17370.8388-0.0534-0.04640.0811-0.04640.02440.00790.08110.00790.0290.0065-0.00620.0069-0.034-0.0047-0.0106-9.2092-12.124510.1303
21.13790.5544-0.49331.2297-0.19961.5751-0.1089-0.1854-0.0922-0.18540.1181-0.0822-0.0922-0.0822-0.00920.00980.0071-0.0224-0.02530.01280.0031-13.495510.882814.0508
30.52150.2327-0.20250.88510.32070.941-0.02440.12120.07140.12120.07620.09740.07140.0974-0.05180.00660.0071-0.001-0.0156-0.019-0.0119-0.6156-0.137427.24
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|* }A8 - 157
2X-RAY DIFFRACTION1{ A|* }A4000
3X-RAY DIFFRACTION2{ B|* }B10 - 157
4X-RAY DIFFRACTION3{ C|* }C3 - 157

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