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- PDB-4twt: Human TNFa dimer in complex with the semi-synthetic bicyclic pept... -

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Basic information

Entry
Database: PDB / ID: 4twt
TitleHuman TNFa dimer in complex with the semi-synthetic bicyclic peptide M21
Components
  • ALA-CYS-PRO-PRO-CYS-LEU-TRP-GLN-VAL-LEU-CYS-GLY
  • Tumor necrosis factor
KeywordsCytokine/inhibitor / Tumor Necrosis Factor-alpha / Bicyclo Compounds / Peptides / cytokine-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 / : / 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 / 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 / response to isolation stress / negative regulation of vascular wound healing / negative regulation of bicellular tight junction assembly / negative regulation of amyloid-beta clearance / 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 / sequestering of triglyceride / positive regulation of interleukin-18 production / positive regulation of action potential / TNF signaling / positive regulation of protein transport / 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 / positive regulation of neuroinflammatory response / leukocyte tethering or rolling / positive regulation of synoviocyte proliferation / response to fructose / positive regulation of fever generation / positive regulation of mononuclear cell migration / negative regulation of myoblast differentiation / negative regulation of glucose import / regulation of establishment of endothelial barrier / endothelial cell apoptotic process / macrophage activation involved in immune response / positive regulation of protein localization to cell surface / TNFR1-mediated ceramide production / negative regulation of oxidative phosphorylation / positive regulation of osteoclast differentiation / positive regulation of cytokine production involved in inflammatory response / tumor necrosis factor receptor binding / negative regulation of systemic arterial blood pressure / positive regulation of extrinsic apoptotic signaling pathway / positive regulation of chemokine (C-X-C motif) ligand 2 production / positive regulation of programmed cell death / regulation of immunoglobulin production / positive regulation of hepatocyte proliferation / positive regulation of heterotypic cell-cell adhesion / positive regulation of protein-containing complex disassembly / positive regulation of podosome assembly / positive regulation of membrane protein ectodomain proteolysis / regulation of canonical NF-kappaB signal transduction / 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 / response to L-glutamate / cortical actin cytoskeleton organization / negative regulation of heart rate / positive regulation of amyloid-beta formation / positive regulation of DNA biosynthetic process / 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 / positive regulation of cysteine-type endopeptidase activity involved in apoptotic process / negative regulation of interleukin-6 production / phagocytic cup / antiviral innate immune response / negative regulation of apoptotic signaling pathway / humoral immune response / negative regulation of blood vessel endothelial cell migration / negative regulation of lipid storage / 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. / TNF(Tumour Necrosis Factor) family / Tumour necrosis factor domain / Tumor necrosis factor (TNF) homology domain (THD) profile. / Jelly Rolls - #40 / 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 / Tumour necrosis factor domain / Tumor necrosis factor (TNF) homology domain (THD) profile. / Jelly Rolls - #40 / Tumour necrosis factor-like domain superfamily / Jelly Rolls / Sandwich / Mainly Beta
Similarity search - Domain/homology
(2,4,6-trimethylbenzene-1,3,5-triyl)trimethanol / Tumor necrosis factor
Similarity search - Component
Biological speciesHomo sapiens (human)
synthetic construct (others)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.85 Å
AuthorsLuzi, S. / Kondo, Y. / Bernard, E. / Stadler, L. / Winter, G. / Holliger, P.
CitationJournal: Protein Eng.Des.Sel. / Year: 2015
Title: Subunit disassembly and inhibition of TNF alpha by a semi-synthetic bicyclic peptide.
Authors: Luzi, S. / Kondo, Y. / Bernard, E. / Stadler, L.K. / Vaysburd, M. / Winter, G. / Holliger, P.
History
DepositionJul 1, 2014Deposition site: RCSB / Processing site: PDBE
Revision 1.0Feb 4, 2015Provider: repository / Type: Initial release
Revision 1.1Dec 20, 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 / struct_ncs_dom_lim
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_id

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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
E: ALA-CYS-PRO-PRO-CYS-LEU-TRP-GLN-VAL-LEU-CYS-GLY
F: ALA-CYS-PRO-PRO-CYS-LEU-TRP-GLN-VAL-LEU-CYS-GLY
C: Tumor necrosis factor
D: Tumor necrosis factor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)73,03514
Polymers72,0626
Non-polymers9738
Water64936
1
A: Tumor necrosis factor
B: Tumor necrosis factor
E: ALA-CYS-PRO-PRO-CYS-LEU-TRP-GLN-VAL-LEU-CYS-GLY
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,6108
Polymers36,0313
Non-polymers5795
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4350 Å2
ΔGint-24 kcal/mol
Surface area13980 Å2
MethodPISA
2
F: ALA-CYS-PRO-PRO-CYS-LEU-TRP-GLN-VAL-LEU-CYS-GLY
C: Tumor necrosis factor
D: Tumor necrosis factor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,4256
Polymers36,0313
Non-polymers3943
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3700 Å2
ΔGint-27 kcal/mol
Surface area13390 Å2
MethodPISA
Unit cell
Length a, b, c (Å)78.444, 78.444, 230.375
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number154
Space group name H-MP3221
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B
12A
22C
13A
23D
14B
24C
15B
25D
16E
26F
17C
27D

NCS domain segments:

Component-ID: _ / Refine code: _

Dom-IDEns-IDBeg auth comp-IDBeg label comp-IDEnd auth comp-IDEnd label comp-IDAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11ASPASPLEULEUAA10 - 15710 - 157
21ASPASPLEULEUBB10 - 15710 - 157
12SERSERLEULEUAA9 - 1579 - 157
22SERSERLEULEUCE9 - 1579 - 157
13SERSERLEULEUAA9 - 1579 - 157
23SERSERLEULEUDF9 - 1579 - 157
14ASPASPLEULEUBB10 - 15710 - 157
24ASPASPLEULEUCE10 - 15710 - 157
15ASPASPLEULEUBB10 - 15710 - 157
25ASPASPLEULEUDF10 - 15710 - 157
16ALAALAGLYGLYEC1 - 121 - 12
26ALAALAGLYGLYFD1 - 121 - 12
17SERSERLEULEUCE9 - 1579 - 157
27SERSERLEULEUDF9 - 1579 - 157

NCS ensembles :
ID
1
2
3
4
5
6
7

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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.: 4 / Fragment: UNP Residues 77-233
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: Protein/peptide ALA-CYS-PRO-PRO-CYS-LEU-TRP-GLN-VAL-LEU-CYS-GLY / peptide M21


Mass: 1289.588 Da / Num. of mol.: 2 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)
#3: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C3H8O3
#4: Chemical ChemComp-38A / (2,4,6-trimethylbenzene-1,3,5-triyl)trimethanol


Mass: 210.270 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C12H18O3
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 36 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 2.84 Å3/Da / Density % sol: 56.68 % / Description: hexagonal
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 6.5
Details: 25.5% PEG 8000, 0.085 M Na Cacodylate pH 6.5, 0.17M Ammonium Sulfate, 15% Glycerol.

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04-1 / Wavelength: 0.98 Å
DetectorType: DECTRIS PILATUS 2M / Detector: PIXEL / Date: May 6, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.98 Å / Relative weight: 1
ReflectionResolution: 2.85→46.08 Å / Num. obs: 19797 / % possible obs: 99 % / Redundancy: 7.7 % / Rmerge(I) obs: 0.144 / Net I/σ(I): 9.1
Reflection shellResolution: 2.85→3.02 Å / Redundancy: 8 % / Rmerge(I) obs: 1.247 / Mean I/σ(I) obs: 2 / % possible all: 99.1

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Processing

Software
NameVersionClassification
REFMAC5.8.0073refinement
Aimlessdata scaling
iMOSFLMdata reduction
PHASERphasing
Cootmodel building
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1TNF

1tnf


Resolution: 2.85→76.79 Å / Cor.coef. Fo:Fc: 0.931 / Cor.coef. Fo:Fc free: 0.895 / SU B: 18.94 / SU ML: 0.355 / Cross valid method: THROUGHOUT / ESU R: 3.012 / ESU R Free: 0.414 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.28601 1005 5.1 %RANDOM
Rwork0.22593 ---
obs0.22887 18737 98.65 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 81.851 Å2
Baniso -1Baniso -2Baniso -3
1-0.31 Å20.15 Å20 Å2
2--0.31 Å2-0 Å2
3----1 Å2
Refinement stepCycle: 1 / Resolution: 2.85→76.79 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4533 0 60 36 4629
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.0194696
X-RAY DIFFRACTIONr_bond_other_d0.0070.024509
X-RAY DIFFRACTIONr_angle_refined_deg1.6921.9786383
X-RAY DIFFRACTIONr_angle_other_deg2.5963.00110315
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.8925574
X-RAY DIFFRACTIONr_dihedral_angle_2_deg39.50724.55200
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.15115726
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.9421522
X-RAY DIFFRACTIONr_chiral_restr0.0880.2725
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.0215283
X-RAY DIFFRACTIONr_gen_planes_other0.0060.021057
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it5.8018.1722331
X-RAY DIFFRACTIONr_mcbond_other5.8018.1722331
X-RAY DIFFRACTIONr_mcangle_it9.17312.2192892
X-RAY DIFFRACTIONr_mcangle_other9.17112.222893
X-RAY DIFFRACTIONr_scbond_it5.7018.4422365
X-RAY DIFFRACTIONr_scbond_other5.6938.4432365
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other8.72212.5213492
X-RAY DIFFRACTIONr_long_range_B_refined14.88176.39318211
X-RAY DIFFRACTIONr_long_range_B_other14.88176.39418210
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
Refine LS restraints NCS

Refine-ID: X-RAY DIFFRACTION / Type: interatomic distance / Weight position: 0.05

Ens-IDDom-IDAuth asym-IDNumberRms dev position (Å)
11A72530.16
12B72530.16
21A75400.16
22C75400.16
31A65670.18
32D65670.18
41B70420.17
42C70420.17
51B67910.16
52D67910.16
61E4760.12
62F4760.12
71C66210.18
72D66210.18
LS refinement shellResolution: 2.85→2.924 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.442 74 -
Rwork0.371 1360 -
obs--98.9 %

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