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- PDB-5m2i: Structure of human Tumor Necrosis Factor (TNF) in complex with th... -

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Basic information

Entry
Database: PDB / ID: 5m2i
TitleStructure of human Tumor Necrosis Factor (TNF) in complex with the Llama VHH1
Components
  • Tumor necrosis factor
  • VHH1
KeywordsCYTOKINE / human Tumor Necrosis Factor (TNF) Llama VHH1
Function / homology
Function and homology information


response to Gram-negative bacterium / negative regulation of L-glutamate import across plasma membrane / negative regulation of bile acid secretion / positive regulation of neutrophil activation / negative regulation of branching involved in lung morphogenesis / positive regulation of interleukin-33 production / positive regulation of fractalkine production / positive regulation of blood microparticle formation / positive regulation of chronic inflammatory response to antigenic stimulus / response to 3,3',5-triiodo-L-thyronine ...response to Gram-negative bacterium / negative regulation of L-glutamate import across plasma membrane / negative regulation of bile acid secretion / positive regulation of neutrophil activation / negative regulation of branching involved in lung morphogenesis / positive regulation of interleukin-33 production / positive regulation of fractalkine 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 leukocyte adhesion to arterial endothelial cell / positive regulation of protein transport / positive regulation of vitamin D biosynthetic process / positive regulation of translational initiation by iron / : / chronic inflammatory response to antigenic stimulus / regulation of endothelial cell apoptotic process / response to macrophage colony-stimulating factor / 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 / response to gold nanoparticle / negative regulation of myelination / TNF signaling / negative regulation of vascular wound healing / negative regulation of cytokine production involved in immune response / negative regulation of amyloid-beta clearance / positive regulation of hair follicle development / inflammatory response to wounding / death receptor agonist activity / positive regulation of action potential / positive regulation of interleukin-18 production / epithelial cell proliferation involved in salivary gland morphogenesis / toll-like receptor 3 signaling pathway / positive regulation of JUN kinase activity / vascular endothelial growth factor production / negative regulation of D-glucose import across plasma membrane / leukocyte migration involved in inflammatory response / embryonic digestive tract development / positive regulation of fever generation / response to fructose / positive regulation of synoviocyte proliferation / positive regulation of calcineurin-NFAT signaling cascade / necroptotic signaling pathway / leukocyte tethering or rolling / positive regulation of mononuclear cell migration / positive regulation of hepatocyte proliferation / negative regulation of myoblast differentiation / regulation of establishment of endothelial barrier / positive regulation of protein-containing complex disassembly / endothelial cell apoptotic process / negative regulation of oxidative phosphorylation / positive regulation of protein localization to cell surface / positive regulation of osteoclast differentiation / cellular response to toxic substance / positive regulation of heterotypic cell-cell adhesion / macrophage activation involved in immune response / tumor necrosis factor receptor binding / negative regulation of systemic arterial blood pressure / positive regulation of macrophage derived foam cell differentiation / positive regulation of cytokine production involved in inflammatory response / negative regulation of mitotic cell cycle / regulation of metabolic process / regulation of immunoglobulin production / positive regulation of podosome assembly / positive regulation of chemokine (C-X-C motif) ligand 2 production / regulation of fat cell differentiation / positive regulation of programmed cell death / positive regulation of membrane protein ectodomain proteolysis / regulation of canonical NF-kappaB signal transduction / response to L-glutamate / positive regulation of neuroinflammatory response / positive regulation of leukocyte adhesion to vascular endothelial cell / positive regulation of extrinsic apoptotic signaling pathway / TNFR1-induced proapoptotic signaling / TNFR1-mediated ceramide production / regulation of reactive oxygen species metabolic process / positive regulation of DNA biosynthetic process / negative regulation of heart rate / positive regulation of amyloid-beta formation / negative regulation of viral genome replication / negative regulation of bicellular tight junction assembly / response to isolation stress / negative regulation of fat cell differentiation / regulation of synapse organization / negative regulation of endothelial cell proliferation / positive regulation of MAP kinase activity / Interleukin-10 signaling / humoral immune response / negative regulation of interleukin-6 production / negative regulation of blood vessel endothelial cell migration / negative regulation of apoptotic signaling pathway / extrinsic apoptotic signaling pathway via death domain receptors / positive regulation of glial cell proliferation / negative regulation of lipid storage / cell surface receptor signaling pathway via JAK-STAT / negative regulation of extrinsic apoptotic signaling pathway in absence of ligand / negative regulation of osteoblast differentiation / detection of mechanical stimulus involved in sensory perception of pain / negative regulation of lipid catabolic process
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 / Jelly Rolls - #40 / Tumour necrosis factor domain / Tumor necrosis factor (TNF) homology domain (THD) profile. / Tumour necrosis factor-like domain superfamily ...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 / Jelly Rolls - #40 / Tumour necrosis factor domain / Tumor necrosis factor (TNF) homology domain (THD) profile. / Tumour necrosis factor-like domain superfamily / Jelly Rolls / Immunoglobulins / Immunoglobulin-like / Sandwich / Mainly Beta
Similarity search - Domain/homology
Tumor necrosis factor
Similarity search - Component
Biological speciesHomo sapiens (human)
Lama glama (llama)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.15 Å
AuthorsCambillau, C. / Spinelli, S. / Desmyter, A. / de Haard, H.
CitationJournal: Front Immunol / Year: 2017
Title: Bivalent Llama Single-Domain Antibody Fragments against Tumor Necrosis Factor Have Picomolar Potencies due to Intramolecular Interactions.
Authors: Beirnaert, E. / Desmyter, A. / Spinelli, S. / Lauwereys, M. / Aarden, L. / Dreier, T. / Loris, R. / Silence, K. / Pollet, C. / Cambillau, C. / de Haard, H.
History
DepositionOct 13, 2016Deposition site: PDBE / Processing site: PDBE
Revision 1.0Aug 30, 2017Provider: repository / Type: Initial release
Revision 1.1Sep 6, 2017Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Jan 17, 2024Group: 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 1.3Nov 6, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

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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
G: VHH1
H: VHH1
I: VHH1
J: VHH1
K: VHH1
L: VHH1


Theoretical massNumber of molelcules
Total (without water)184,72012
Polymers184,72012
Non-polymers00
Water13,457747
1
A: Tumor necrosis factor
B: Tumor necrosis factor
C: Tumor necrosis factor
G: VHH1
H: VHH1
I: VHH1


Theoretical massNumber of molelcules
Total (without water)92,3606
Polymers92,3606
Non-polymers00
Water1086
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area13520 Å2
ΔGint-64 kcal/mol
Surface area30730 Å2
MethodPISA
2
D: Tumor necrosis factor
E: Tumor necrosis factor
F: Tumor necrosis factor
J: VHH1
K: VHH1
L: VHH1


Theoretical massNumber of molelcules
Total (without water)92,3606
Polymers92,3606
Non-polymers00
Water1086
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area13490 Å2
ΔGint-64 kcal/mol
Surface area30560 Å2
MethodPISA
Unit cell
Length a, b, c (Å)110.330, 117.410, 141.890
Angle α, β, γ (deg.)90.00, 90.00, 90.00
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: 17370.658 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 (bacteria) / References: UniProt: P01375
#2: Antibody
VHH1


Mass: 13415.949 Da / Num. of mol.: 6
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Lama glama (llama) / Production host: Escherichia coli BL21
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 747 / 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: 2.5 Å3/Da / Density % sol: 50.86 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 7.5
Details: mixed 100 nL of protein 8 mg per ml in HEPES 10 mM pH 7.0 with 100 nL of precipitant solution containing 20% PEG3000 and 0.2M NaCl and 0.1M HEPES at pH 7.5.

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID14-1 / Wavelength: 0.931 Å
DetectorType: ADSC QUANTUM 4 / Detector: CCD / Date: Oct 18, 2005
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.931 Å / Relative weight: 1
ReflectionResolution: 2.15→50 Å / Num. obs: 100770 / % possible obs: 99.5 % / Redundancy: 4.15 % / Biso Wilson estimate: 36.47 Å2 / CC1/2: 0.997 / Rmerge(I) obs: 0.127 / Net I/σ(I): 8.8
Reflection shellResolution: 2.15→2.21 Å / Redundancy: 4 % / Rmerge(I) obs: 1.11 / Mean I/σ(I) obs: 1.5 / CC1/2: 0.72 / % possible all: 95.6

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Processing

Software
NameVersionClassification
BUSTER2.10.1refinement
XDSdata reduction
SCALAdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1TNF

1tnf


Resolution: 2.15→48.68 Å / Cor.coef. Fo:Fc: 0.9427 / Cor.coef. Fo:Fc free: 0.9292 / SU R Cruickshank DPI: 0.235 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.24 / SU Rfree Blow DPI: 0.185 / SU Rfree Cruickshank DPI: 0.186
RfactorNum. reflection% reflectionSelection details
Rfree0.2376 5026 5 %RANDOM
Rwork0.2068 ---
obs0.2083 100502 99.86 %-
Displacement parametersBiso mean: 44.22 Å2
Baniso -1Baniso -2Baniso -3
1--9.2125 Å20 Å20 Å2
2--5.1676 Å20 Å2
3---4.0448 Å2
Refine analyzeLuzzati coordinate error obs: 0.317 Å
Refinement stepCycle: 1 / Resolution: 2.15→48.68 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms12521 0 0 747 13268
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.00812819HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.1717438HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d4297SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes322HARMONIC2
X-RAY DIFFRACTIONt_gen_planes1858HARMONIC5
X-RAY DIFFRACTIONt_it12819HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.36
X-RAY DIFFRACTIONt_other_torsion21.7
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion1601SEMIHARMONIC5
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_contact14497SEMIHARMONIC4
LS refinement shellResolution: 2.15→2.21 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.2588 369 5.01 %
Rwork0.233 7002 -
all0.2343 7371 -
obs--99.86 %
Refinement TLS params.

Method: refined / 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)
10.3086-0.644-0.1911.8939-0.18041.36390.00620.0824-0.0457-0.03560.08110.00080.0220.047-0.08730.08790.0002-0.0152-0.1065-0.0517-0.0303-2.00723.0232-51.1148
20.1552-0.2876-0.11560.4726-0.06141.26010.0134-0.0014-0.0567-0.0056-0.03220.01660.05550.07360.01880.16590.0206-0.0028-0.088-0.0025-0.07275.92151.7096-30.893
30.97490.26020.19190.61370.02661.3143-0.0042-0.02410.02620.04180.0183-0.0511-0.0280.0183-0.01410.10390.04760.0732-0.06420.0366-0.0594-0.270620.9633-39.1217
40.37220.89490.28862.06820.33351.40680.0035-0.07140.06240.02510.06180.0173-0.02870.0483-0.06530.0653-0.0112-0.0148-0.0936-0.0467-0.0312-1.94-27.4681-90.8468
50.3298-0.03680.20740.757-0.2241.08170.01050.00150.05120.0251-0.02650.0166-0.07010.09520.0160.1076-0.02940.0031-0.0418-0.013-0.05456.5723-26.1735-110.868
60.8224-0.48540.02320.63040.17351.4743-0.00750.0201-0.0401-0.0385-0.0114-0.0540.03810.00340.01890.061-0.0301-0.0653-0.04940.0307-0.0433-0.1919-45.425-102.739
70.373-0.13190.83141.39220.10092.51540.00040.005-0.01110.0213-0.021-0.0298-0.0079-0.01170.02050.2213-0.00880.0038-0.13930.0188-0.11876.87659.2296-8.0579
800.5165-0.37744.03030.99151.46310.0017-0.00890.05060.0082-0.00890.02660.02350.01220.00720.180.0347-0.0891-0.162-0.0708-0.0523-6.5016-20.0025-54.8114
90.424-0.50020.86393.2486-0.19641.6827-0.0156-0.0399-0.0247-0.01470.04840.0569-0.0377-0.0186-0.03280.10450.0170.0541-0.10780.0062-0.0838-13.668235.1386-52.8483
100.4930.5391-1.17561.49030.11532.5258-0.0033-0.00230.0204-0.0269-0.0176-0.02890.01490.02720.02080.13670.0261-0.0182-0.09860.0162-0.08866.9969-33.6168-133.794
110-0.12130.3784.01310.89091.4206-0.0010.0059-0.0490.01110.00170.0194-0.02860.0116-0.00080.1496-0.02270.0502-0.1464-0.0756-0.0385-6.4005-4.3997-86.9883
120.16310.643-0.57883.17650.3742.5461-0.01960.04040.04220.02850.03120.07670.0597-0.0236-0.01150.213-0.0096-0.0179-0.16190.0047-0.1236-13.7656-59.4581-89.0684
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1{ A|* }
2X-RAY DIFFRACTION2{ B|* }
3X-RAY DIFFRACTION3{ C|* }
4X-RAY DIFFRACTION4{ D|* }
5X-RAY DIFFRACTION5{ E|* }
6X-RAY DIFFRACTION6{ F|* }
7X-RAY DIFFRACTION7{ G|* }
8X-RAY DIFFRACTION8{ H|* }
9X-RAY DIFFRACTION9{ I|* }
10X-RAY DIFFRACTION10{ J|* }
11X-RAY DIFFRACTION11{ K|* }
12X-RAY DIFFRACTION12{ L|* }

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