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- PDB-6x85: Crystal Structure of TNFalpha with indolinone compound 9 -

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Basic information

Entry
Database: PDB / ID: 6x85
TitleCrystal Structure of TNFalpha with indolinone compound 9
ComponentsTumor necrosis factor
KeywordsCYTOKINE / Trimer / inhibitor complex
Function / homology
Function and homology information


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 / 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 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 / positive regulation of chronic inflammatory response to antigenic stimulus / positive regulation of fractalkine production / : / response to macrophage colony-stimulating factor / positive regulation of vitamin D biosynthetic process / positive regulation of leukocyte adhesion to arterial endothelial cell / positive regulation of translational initiation by iron / 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 / response to gold nanoparticle / positive regulation of humoral immune response mediated by circulating immunoglobulin / negative regulation of myosin-light-chain-phosphatase activity / positive regulation of hair follicle development / negative regulation of myelination / death receptor agonist activity / negative regulation of amyloid-beta clearance / negative regulation of vascular wound healing / negative regulation of bicellular tight junction assembly / response to isolation stress / negative regulation of cytokine production involved in immune response / inflammatory response to wounding / cellular response to toxic substance / positive regulation of calcidiol 1-monooxygenase activity / positive regulation of I-kappaB phosphorylation / positive regulation of action potential / sequestering of triglyceride / TNF signaling / 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 / embryonic digestive tract development / positive regulation of superoxide dismutase activity / leukocyte migration involved in inflammatory response / necroptotic signaling pathway / vascular endothelial growth factor production / positive regulation of calcineurin-NFAT signaling cascade / leukocyte tethering or rolling / positive regulation of neuroinflammatory response / positive regulation of synoviocyte proliferation / response to fructose / positive regulation of fever generation / negative regulation of myoblast differentiation / positive regulation of mononuclear cell migration / positive regulation of protein localization to cell surface / negative regulation of glucose import / TNFR1-mediated ceramide production / endothelial cell apoptotic process / regulation of establishment of endothelial barrier / macrophage activation involved in immune response / positive regulation of osteoclast differentiation / negative regulation of oxidative phosphorylation / positive regulation of cytokine production involved in inflammatory response / 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 programmed cell death / positive regulation of hepatocyte proliferation / positive regulation of extrinsic apoptotic signaling pathway / regulation of immunoglobulin production / positive regulation of heterotypic cell-cell adhesion / 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 / regulation of fat cell differentiation / 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 heart rate / positive regulation of amyloid-beta formation / 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 / regulation of insulin secretion / negative regulation of interleukin-6 production / phagocytic cup / antiviral innate immune response / positive regulation of cysteine-type endopeptidase activity involved in apoptotic process / negative regulation of apoptotic signaling pathway / humoral immune response / negative regulation of lipid storage / negative regulation of blood vessel endothelial cell migration / skeletal muscle contraction
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. / Tumor necrosis factor (TNF) homology domain (THD) profile. / TNF(Tumour Necrosis Factor) family / Tumour necrosis factor domain / Tumour necrosis factor-like domain superfamily
Similarity search - Domain/homology
Chem-UTV / Tumor necrosis factor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.85 Å
AuthorsLongenecker, K.L. / Stoll, V.S.
CitationJournal: J.Med.Chem. / Year: 2021
Title: Development of Orally Efficacious Allosteric Inhibitors of TNF alpha via Fragment-Based Drug Design.
Authors: Dietrich, J.D. / Longenecker, K.L. / Wilson, N.S. / Goess, C. / Panchal, S.C. / Swann, S.L. / Petros, A.M. / Hobson, A.D. / Ihle, D. / Song, D. / Richardson, P. / Comess, K.M. / Cox, P.B. / ...Authors: Dietrich, J.D. / Longenecker, K.L. / Wilson, N.S. / Goess, C. / Panchal, S.C. / Swann, S.L. / Petros, A.M. / Hobson, A.D. / Ihle, D. / Song, D. / Richardson, P. / Comess, K.M. / Cox, P.B. / Dombrowski, A. / Sarris, K. / Donnelly-Roberts, D.L. / Duignan, D.B. / Gomtsyan, A. / Jung, P. / Krueger, A.C. / Mathieu, S. / McClure, A. / Stoll, V.S. / Wetter, J. / Mankovich, J.A. / Hajduk, P.J. / Vasudevan, A. / Stoffel, R.H. / Sun, C.
History
DepositionJun 1, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 13, 2021Provider: repository / Type: Initial release
Revision 1.1Jan 27, 2021Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.year / _citation_author.identifier_ORCID
Revision 1.2Oct 18, 2023Group: 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

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Assembly

Deposited unit
A: Tumor necrosis factor
B: Tumor necrosis factor
C: Tumor necrosis factor
D: Tumor necrosis factor
E: Tumor necrosis factor
F: Tumor necrosis factor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)105,3287
Polymers105,0116
Non-polymers3171
Water0
1
A: Tumor necrosis factor
B: Tumor necrosis factor
C: Tumor necrosis factor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)52,8234
Polymers52,5063
Non-polymers3171
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5100 Å2
ΔGint-23 kcal/mol
Surface area18950 Å2
MethodPISA
2
D: Tumor necrosis factor
E: Tumor necrosis factor
F: Tumor necrosis factor


Theoretical massNumber of molelcules
Total (without water)52,5063
Polymers52,5063
Non-polymers00
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5880 Å2
ΔGint-31 kcal/mol
Surface area17510 Å2
MethodPISA
Unit cell
Length a, b, c (Å)252.508, 65.672, 54.241
Angle α, β, γ (deg.)90.000, 95.100, 90.000
Int Tables number5
Space group name H-MC121

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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.: 6
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TNF, TNFA, TNFSF2 / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: P01375
#2: Chemical ChemComp-UTV / 1-{[2-(difluoromethoxy)phenyl]methyl}-2,2-dimethyl-1,2-dihydro-3H-indol-3-one


Mass: 317.330 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H17F2NO2 / Feature type: SUBJECT OF INVESTIGATION
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: 2.13 Å3/Da / Density % sol: 42.33 %
Crystal growTemperature: 293 K / Method: vapor diffusion / pH: 6.5
Details: 15% PEG 8000, 0.2M magnesium acetate, 0.05M sodium cacodylate, pH 6.5

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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: Feb 10, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.691→54.026 Å / Num. obs: 24547 / % possible obs: 98.9 % / Redundancy: 3.4 % / Biso Wilson estimate: 95.55 Å2 / Rmerge(I) obs: 0.041 / Net I/σ(I): 14.6
Reflection shellResolution: 2.691→2.7 Å / Redundancy: 3.6 % / Mean I/σ(I) obs: 2.4 / Num. unique obs: 999 / Rrim(I) all: 0.42 / % possible all: 99.2

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Processing

Software
NameVersionClassification
XDS20171218data reduction
Aimless0.7.4data scaling
BUSTER2.11.7refinement
PDB_EXTRACT3.25data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1tnf

1tnf


Resolution: 2.85→29.11 Å / Cor.coef. Fo:Fc: 0.931 / Cor.coef. Fo:Fc free: 0.901 / Cross valid method: THROUGHOUT / σ(F): 0 / SU Rfree Blow DPI: 0.39
RfactorNum. reflection% reflectionSelection details
Rfree0.252 1025 4.94 %RANDOM
Rwork0.198 ---
obs0.201 20745 99 %-
Displacement parametersBiso max: 221.4 Å2 / Biso mean: 98.71 Å2 / Biso min: 42.38 Å2
Baniso -1Baniso -2Baniso -3
1-9.6617 Å20 Å26.581 Å2
2---25.8464 Å20 Å2
3---16.1847 Å2
Refine analyzeLuzzati coordinate error obs: 0.37 Å
Refinement stepCycle: final / Resolution: 2.85→29.11 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6576 0 23 0 6599
Biso mean--60.64 --
Num. residues----842
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d2271SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes1148HARMONIC5
X-RAY DIFFRACTIONt_it6748HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion850SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact7090SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d6748HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg9188HARMONIC21.21
X-RAY DIFFRACTIONt_omega_torsion3.17
X-RAY DIFFRACTIONt_other_torsion21.32
LS refinement shellResolution: 2.85→2.87 Å / Rfactor Rfree error: 0 / Total num. of bins used: 50
RfactorNum. reflection% reflection
Rfree0.2382 17 4.1 %
Rwork0.2287 398 -
all0.2291 415 -
obs--96.58 %

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