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- PDB-6x83: Crystal Structure of TNFalpha with fragment compound 6 -

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Basic information

Entry
Database: PDB / ID: 6x83
TitleCrystal Structure of TNFalpha with fragment compound 6
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 / positive regulation of fractalkine production / 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 / response to 3,3',5-triiodo-L-thyronine ...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 / positive regulation of fractalkine production / 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 / response to 3,3',5-triiodo-L-thyronine / positive regulation of protein transport / positive regulation of leukocyte adhesion to arterial endothelial cell / positive regulation of vitamin D biosynthetic process / positive regulation of translational initiation by iron / regulation of membrane lipid metabolic process / regulation of endothelial cell apoptotic process / response to macrophage colony-stimulating factor / chronic inflammatory response to antigenic stimulus / regulation of branching involved in salivary gland morphogenesis / negative regulation of protein-containing complex disassembly / positive regulation of humoral immune response mediated by circulating immunoglobulin / positive regulation of hair follicle development / negative regulation of myelination / response to gold nanoparticle / negative regulation of vascular wound healing / negative regulation of cytokine production involved in immune response / negative regulation of amyloid-beta clearance / positive regulation of interleukin-18 production / inflammatory response to wounding / death receptor agonist activity / positive regulation of action potential / TNF signaling / epithelial cell proliferation involved in salivary gland morphogenesis / toll-like receptor 3 signaling pathway / negative regulation of D-glucose import / embryonic digestive tract development / leukocyte migration involved in inflammatory response / vascular endothelial growth factor production / positive regulation of fever generation / response to fructose / positive regulation of neuroinflammatory response / positive regulation of synoviocyte proliferation / necroptotic signaling pathway / positive regulation of calcineurin-NFAT signaling cascade / positive regulation of mononuclear cell migration / leukocyte tethering or rolling / positive regulation of hepatocyte proliferation / 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 / macrophage activation involved in immune response / negative regulation of systemic arterial blood pressure / positive regulation of osteoclast differentiation / tumor necrosis factor receptor binding / positive regulation of heterotypic cell-cell adhesion / positive regulation of macrophage derived foam cell differentiation / positive regulation of cytokine production involved in inflammatory response / regulation of immunoglobulin production / TNFR1-mediated ceramide production / positive regulation of programmed cell death / negative regulation of mitotic cell cycle / positive regulation of podosome assembly / positive regulation of membrane protein ectodomain proteolysis / positive regulation of chemokine (C-X-C motif) ligand 2 production / regulation of fat cell differentiation / response to L-glutamate / regulation of canonical NF-kappaB signal transduction / positive regulation of extrinsic apoptotic signaling pathway / positive regulation of leukocyte adhesion to vascular endothelial cell / TNFR1-induced proapoptotic signaling / negative regulation of bicellular tight junction assembly / regulation of metabolic process / regulation of reactive oxygen species metabolic process / positive regulation of DNA biosynthetic process / negative regulation of heart rate / negative regulation of viral genome replication / positive regulation of amyloid-beta formation / response to isolation stress / negative regulation of fat cell differentiation / regulation of synapse organization / negative regulation of endothelial cell proliferation / positive regulation of JUN kinase activity / positive regulation of MAP kinase activity / Interleukin-10 signaling / negative regulation of interleukin-6 production / humoral immune response / negative regulation of apoptotic signaling pathway / negative regulation of blood vessel endothelial cell migration / positive regulation of glial cell proliferation / negative regulation of lipid storage / extrinsic apoptotic signaling pathway via death domain receptors / cell surface receptor signaling pathway via JAK-STAT / negative regulation of extrinsic apoptotic signaling pathway in absence of ligand / skeletal muscle contraction / negative regulation of osteoblast differentiation / 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
1-benzyl-1H-benzimidazole / Tumor necrosis factor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.83 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)105,84410
Polymers105,0116
Non-polymers8334
Water2,648147
1
A: Tumor necrosis factor
B: Tumor necrosis factor
C: Tumor necrosis factor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)52,9225
Polymers52,5063
Non-polymers4172
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5400 Å2
ΔGint-23 kcal/mol
Surface area18190 Å2
MethodPISA
2
D: Tumor necrosis factor
E: Tumor necrosis factor
F: Tumor necrosis factor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)52,9225
Polymers52,5063
Non-polymers4172
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5020 Å2
ΔGint-28 kcal/mol
Surface area17130 Å2
MethodPISA
Unit cell
Length a, b, c (Å)288.773, 54.480, 67.734
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number18
Space group name H-MP21212

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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-UTS / 1-benzyl-1H-benzimidazole


Mass: 208.258 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C14H12N2 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 147 / 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: 2.54 Å3/Da / Density % sol: 51.52 %
Crystal growTemperature: 293 K / Method: vapor diffusion / pH: 6.5
Details: 15% PEG8000, 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 22, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.83→144 Å / Num. obs: 25819 / % possible obs: 97.3 % / Redundancy: 6 % / Biso Wilson estimate: 75.54 Å2 / Rmerge(I) obs: 0.16 / Net I/σ(I): 12
Reflection shellResolution: 2.83→2.88 Å / Rmerge(I) obs: 1 / Num. unique obs: 1308

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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: 2.83→32.97 Å / Cor.coef. Fo:Fc: 0.874 / Cor.coef. Fo:Fc free: 0.847 / Cross valid method: THROUGHOUT / σ(F): 0 / SU Rfree Blow DPI: 0.373
RfactorNum. reflection% reflectionSelection details
Rfree0.261 1335 5.17 %RANDOM
Rwork0.206 ---
obs0.208 25819 97.3 %-
Displacement parametersBiso max: 166.36 Å2 / Biso mean: 70.86 Å2 / Biso min: 23.52 Å2
Baniso -1Baniso -2Baniso -3
1-24.0303 Å20 Å20 Å2
2--19.5031 Å20 Å2
3----43.5335 Å2
Refine analyzeLuzzati coordinate error obs: 0.43 Å
Refinement stepCycle: final / Resolution: 2.83→32.97 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6339 0 64 147 6550
Biso mean--59.85 54.56 -
Num. residues----809
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d2172SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes1120HARMONIC5
X-RAY DIFFRACTIONt_it6543HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion818SEMIHARMONIC5
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_contact6983SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d6543HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg8889HARMONIC21.24
X-RAY DIFFRACTIONt_omega_torsion3.11
X-RAY DIFFRACTIONt_other_torsion22.63
LS refinement shellResolution: 2.83→2.85 Å / Rfactor Rfree error: 0 / Total num. of bins used: 50
RfactorNum. reflection% reflection
Rfree0.3766 27 5.22 %
Rwork0.3028 490 -
all0.3063 517 -
obs--100 %

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