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- PDB-7jra: HUMAN TNF-ALPHA IN COMPLEX WITH 2-[5-(3-chloro-4-{[(1R)-1-(2-fluo... -

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Basic information

Entry
Database: PDB / ID: 7jra
TitleHUMAN TNF-ALPHA IN COMPLEX WITH 2-[5-(3-chloro-4-{[(1R)-1-(2-fluorophenyl)ethyl]amino}quinolin-6-yl)pyrimidin-2-yl]propan-2-ol
ComponentsTumor necrosis factor
KeywordsCYTOKINE / TUMOR NECROSIS FACTOR ALPHA / TNF / ASYMMETRIC / PROTEIN-PROTEIN INTERACTION INHIBITOR / INHIBITOR / LYMPHOKINE
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 / positive regulation of vitamin D biosynthetic process ...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 / positive regulation of vitamin D biosynthetic process / response to macrophage colony-stimulating factor / 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 / positive regulation of interleukin-18 production / response to gold nanoparticle / positive regulation of humoral immune response mediated by circulating immunoglobulin / epithelial cell proliferation involved in salivary gland morphogenesis / positive regulation of hair follicle development / : / death receptor agonist activity / negative regulation of myelination / negative regulation of vascular wound healing / negative regulation of bicellular tight junction assembly / response to isolation stress / negative regulation of amyloid-beta clearance / negative regulation of cytokine production involved in immune response / inflammatory response to wounding / positive regulation of calcidiol 1-monooxygenase activity / positive regulation of action potential / sequestering of triglyceride / positive regulation of I-kappaB phosphorylation / TNF signaling / positive regulation of protein transport / toll-like receptor 3 signaling pathway / embryonic digestive tract development / leukocyte migration involved in inflammatory response / necroptotic signaling pathway / vascular endothelial growth factor production / regulation of immunoglobulin production / positive regulation of calcineurin-NFAT signaling cascade / response to fructose / positive regulation of neuroinflammatory response / cellular response to toxic substance / positive regulation of mononuclear cell migration / leukocyte tethering or rolling / positive regulation of synoviocyte proliferation / positive regulation of fever generation / negative regulation of myoblast differentiation / negative regulation of D-glucose import / regulation of establishment of endothelial barrier / endothelial cell apoptotic process / macrophage activation involved in immune response / negative regulation of oxidative phosphorylation / positive regulation of protein localization to cell surface / TNFR1-mediated ceramide production / positive regulation of osteoclast differentiation / tumor necrosis factor receptor binding / positive regulation of cytokine production involved in inflammatory response / regulation of metabolic process / negative regulation of systemic arterial blood pressure / positive regulation of heterotypic cell-cell adhesion / positive regulation of protein-containing complex disassembly / positive regulation of extrinsic apoptotic signaling pathway / positive regulation of chemokine (C-X-C motif) ligand 2 production / positive regulation of programmed cell death / positive regulation of podosome assembly / positive regulation of hepatocyte proliferation / regulation of canonical NF-kappaB signal transduction / positive regulation of membrane protein ectodomain proteolysis / positive regulation of leukocyte adhesion to vascular endothelial cell / regulation of fat cell differentiation / regulation of reactive oxygen species metabolic process / TNFR1-induced proapoptotic signaling / response to L-glutamate / cortical actin cytoskeleton organization / negative regulation of heart rate / positive regulation of amyloid-beta formation / negative regulation of viral genome replication / positive regulation of DNA biosynthetic process / regulation of synapse organization / negative regulation of fat cell differentiation / : / negative regulation of endothelial cell proliferation / Interleukin-10 signaling / negative regulation of interleukin-6 production / negative regulation of blood vessel endothelial cell migration / humoral immune response / negative regulation of apoptotic signaling pathway / skeletal muscle contraction / phagocytic cup / negative regulation of lipid storage / negative regulation of mitotic cell cycle / negative regulation of extrinsic apoptotic signaling pathway in absence of ligand / extrinsic apoptotic signaling pathway via death domain receptors
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
Chem-VGY / Tumor necrosis factor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.1 Å
AuthorsSheriff, S.
CitationJournal: J.Med.Chem. / Year: 2020
Title: Biologic-like In Vivo Efficacy with Small Molecule Inhibitors of TNF alpha Identified Using Scaffold Hopping and Structure-Based Drug Design Approaches.
Authors: Xiao, H.Y. / Li, N. / Duan, J.J. / Jiang, B. / Lu, Z. / Ngu, K. / Tino, J. / Kopcho, L.M. / Lu, H. / Chen, J. / Tebben, A.J. / Sheriff, S. / Chang, C.Y. / Yanchunas Jr., J. / Calambur, D. / ...Authors: Xiao, H.Y. / Li, N. / Duan, J.J. / Jiang, B. / Lu, Z. / Ngu, K. / Tino, J. / Kopcho, L.M. / Lu, H. / Chen, J. / Tebben, A.J. / Sheriff, S. / Chang, C.Y. / Yanchunas Jr., J. / Calambur, D. / Gao, M. / Shuster, D.J. / Susulic, V. / Xie, J.H. / Guarino, V.R. / Wu, D.R. / Gregor, K.R. / Goldstine, C.B. / Hynes Jr., J. / Macor, J.E. / Salter-Cid, L. / Burke, J.R. / Shaw, P.J. / Dhar, T.G.M.
History
DepositionAug 11, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 9, 2020Provider: repository / Type: Initial release
Revision 1.1Dec 23, 2020Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.2Jan 13, 2021Group: Database references / Category: citation_author / Item: _citation_author.identifier_ORCID
Revision 1.3Oct 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
Revision 1.4Oct 30, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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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)53,6205
Polymers53,0913
Non-polymers5292
Water3,063170
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5560 Å2
ΔGint-34 kcal/mol
Surface area18660 Å2
MethodPISA
Unit cell
Length a, b, c (Å)54.480, 81.710, 92.970
Angle α, β, γ (deg.)90.000, 90.000, 90.000
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: 17697.055 Da / Num. of mol.: 3 / Mutation: YES
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TNF, TNFA, TNFSF2 / Plasmid: PET28 / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: P01375
#2: Chemical ChemComp-VGY / 2-[5-(3-chloro-4-{[(1R)-1-(2-fluorophenyl)ethyl]amino}quinolin-6-yl)pyrimidin-2-yl]propan-2-ol


Mass: 436.909 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H22ClFN4O / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 170 / 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: 1.95 Å3/Da / Density % sol: 36.89 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: 100 mM HEPES, pH 7.5, 13% (w/v) MePEG5000, 3% (v/v) dioxane

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E SUPERBRIGHT / Wavelength: 1.54 Å
DetectorType: DECTRIS PILATUS 200K / Detector: PIXEL / Date: Sep 10, 2015 / Details: VARIMAX HF ARC)SEC CONFOCAL
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54 Å / Relative weight: 1
ReflectionResolution: 2.1→92.97 Å / Num. obs: 24773 / % possible obs: 99.4 % / Observed criterion σ(I): 0 / Redundancy: 6.3 % / Biso Wilson estimate: 25 Å2 / Rsym value: 0.112 / Net I/σ(I): 12.8
Reflection shellResolution: 2.1→2.21 Å / Redundancy: 5.7 % / Mean I/σ(I) obs: 3.7 / Num. unique obs: 3434 / Rsym value: 0.504 / % possible all: 96.3

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
XDSdata reduction
Aimlessdata scaling
AMoREphasing
BUSTER2.11.6refinement
PDB_EXTRACT3.22data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2AZ5

2az5


Resolution: 2.1→24.21 Å / Cor.coef. Fo:Fc: 0.9354 / Cor.coef. Fo:Fc free: 0.9138 / SU R Cruickshank DPI: 0.237 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.244 / SU Rfree Blow DPI: 0.187 / SU Rfree Cruickshank DPI: 0.186
RfactorNum. reflection% reflectionSelection details
Rfree0.2348 496 2.01 %RANDOM
Rwork0.1953 ---
obs0.1961 24694 99.32 %-
Displacement parametersBiso max: 144.34 Å2 / Biso mean: 29.03 Å2 / Biso min: 7.5 Å2
Baniso -1Baniso -2Baniso -3
1--3.0161 Å20 Å20 Å2
2--1.9963 Å20 Å2
3---1.0198 Å2
Refine analyzeLuzzati coordinate error obs: 0.295 Å
Refinement stepCycle: final / Resolution: 2.1→24.21 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3302 0 37 170 3509
Biso mean--17.69 28.94 -
Num. residues----441
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d1096SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes72HARMONIC2
X-RAY DIFFRACTIONt_gen_planes543HARMONIC5
X-RAY DIFFRACTIONt_it3451HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion449SEMIHARMONIC5
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_contact3963SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d3451HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg4737HARMONIC21.17
X-RAY DIFFRACTIONt_omega_torsion3.9
X-RAY DIFFRACTIONt_other_torsion16.18
LS refinement shellResolution: 2.1→2.19 Å / Total num. of bins used: 12
RfactorNum. reflection% reflection
Rfree0.2085 53 1.87 %
Rwork0.2055 2787 -
all0.2055 2840 -
obs--95.29 %

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