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- PDB-7p3i: Crystal structure of human CD40/TNFRSF5 in complex with the anti-... -

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Basic information

Entry
Database: PDB / ID: 7p3i
TitleCrystal structure of human CD40/TNFRSF5 in complex with the anti-CD40 DARPin protein
Components
  • Darpin
  • Tumor necrosis factor receptor superfamily member 5
KeywordsUNKNOWN FUNCTION / TNFRSF5 / immune-oncology / CD40
Function / homology
Function and homology information


CD154 receptor binding / cellular response to erythropoietin / response to peptide / B cell mediated immunity / immune response-regulating cell surface receptor signaling pathway / positive regulation of protein kinase C signaling / CD40 signaling pathway / varicosity / TNF receptor superfamily (TNFSF) members mediating non-canonical NF-kB pathway / positive regulation of isotype switching to IgG isotypes ...CD154 receptor binding / cellular response to erythropoietin / response to peptide / B cell mediated immunity / immune response-regulating cell surface receptor signaling pathway / positive regulation of protein kinase C signaling / CD40 signaling pathway / varicosity / TNF receptor superfamily (TNFSF) members mediating non-canonical NF-kB pathway / positive regulation of isotype switching to IgG isotypes / CD40 receptor complex / TRIF-dependent toll-like receptor signaling pathway / positive regulation of endothelial cell apoptotic process / B cell activation / response to cobalamin / B cell proliferation / response to type II interferon / defense response to protozoan / positive regulation of blood vessel endothelial cell migration / cellular response to interleukin-1 / positive regulation of B cell proliferation / positive regulation of tyrosine phosphorylation of STAT protein / positive regulation of interleukin-12 production / phosphatidylinositol 3-kinase/protein kinase B signal transduction / antigen binding / TNFR2 non-canonical NF-kB pathway / positive regulation of MAP kinase activity / platelet activation / positive regulation of GTPase activity / intracellular calcium ion homeostasis / cellular response to mechanical stimulus / positive regulation of angiogenesis / Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell / signaling receptor activity / cellular response to tumor necrosis factor / positive regulation of NF-kappaB transcription factor activity / protein-containing complex assembly / positive regulation of canonical NF-kappaB signal transduction / defense response to virus / cellular response to lipopolysaccharide / inflammatory response / positive regulation of protein phosphorylation / protein domain specific binding / external side of plasma membrane / intracellular membrane-bounded organelle / neuronal cell body / ubiquitin protein ligase binding / enzyme binding / cell surface / positive regulation of transcription by RNA polymerase II / extracellular exosome / plasma membrane
Similarity search - Function
Tumour necrosis factor receptor 5 / Tumour necrosis factor receptor 5, N-terminal / TNFR/NGFR family cysteine-rich region domain profile. / TNFR/NGFR cysteine-rich region / TNFR/NGFR family cysteine-rich region signature. / Tumor necrosis factor receptor / nerve growth factor receptor repeats. / TNFR/NGFR cysteine-rich region
Similarity search - Domain/homology
Tumor necrosis factor receptor superfamily member 5
Similarity search - Component
Biological speciesHomo sapiens (human)
synthetic construct (others)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.29 Å
AuthorsMalvezzi, F. / Mangold, S. / Hospodarsch, T. / Reichen, C. / Iss, C. / Lammens, A. / Krapp, S. / Domke, C.
CitationJournal: Cancer Immunol Res / Year: 2022
Title: A Multispecific Anti-CD40 DARPin Construct Induces Tumor-Selective CD40 Activation and Tumor Regression.
Authors: Rigamonti, N. / Veitonmaki, N. / Domke, C. / Barsin, S. / Jetzer, S. / Abdelmotaleb, O. / Bessey, R. / Lekishvili, T. / Malvezzi, F. / Gachechiladze, M. / Behe, M. / Levitsky, V. / Trail, P.A.
History
DepositionJul 7, 2021Deposition site: PDBE / Processing site: PDBE
Revision 1.0Apr 6, 2022Provider: repository / Type: Initial release
Revision 1.1May 11, 2022Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title / _citation_author.identifier_ORCID

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Tumor necrosis factor receptor superfamily member 5
B: Darpin
C: Tumor necrosis factor receptor superfamily member 5
D: Darpin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)72,8406
Polymers72,7944
Non-polymers462
Water3,747208
1
A: Tumor necrosis factor receptor superfamily member 5
B: Darpin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,4203
Polymers36,3972
Non-polymers231
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
C: Tumor necrosis factor receptor superfamily member 5
D: Darpin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,4203
Polymers36,3972
Non-polymers231
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)193.670, 59.564, 81.842
Angle α, β, γ (deg.)90.000, 106.990, 90.000
Int Tables number5
Space group name H-MC121
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21C
12B
22D

NCS domain segments:
Dom-IDComponent-IDEns-IDRefine codeAuth asym-IDAuth seq-ID
1010A25 - 188
2010C25 - 188
1020B13 - 167
2020D13 - 167

NCS ensembles :
ID
1
2

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Components

#1: Protein Tumor necrosis factor receptor superfamily member 5 / B-cell surface antigen CD40 / Bp50 / CD40L receptor / CDw40


Mass: 19654.049 Da / Num. of mol.: 2 / Fragment: >FRAGMENT<
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CD40, TNFRSF5 / Production host: Spodoptera (butterflies/moths) / References: UniProt: P25942
#2: Protein Darpin /


Mass: 16742.986 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) synthetic construct (others) / Production host: Escherichia coli BL21(DE3) (bacteria)
#3: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Na
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 208 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestN

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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: 3.07 Å3/Da / Density % sol: 59.93 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 8.5
Details: 29.9999 %w/v PEG 4K, 0.24 M LiSO4, 0.0999 M TRIS, 0.35 M NaBr

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 0.999812 Å
DetectorType: DECTRIS EIGER2 X 16M / Detector: PIXEL / Date: Jul 8, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.999812 Å / Relative weight: 1
ReflectionResolution: 2.286→92.61 Å / Num. obs: 39800 / % possible obs: 97.8 % / Redundancy: 4.3 % / Rmerge(I) obs: 0.078 / Rsym value: 0.078 / Net I/σ(I): 10.1
Reflection shellResolution: 2.286→2.326 Å / Redundancy: 4.4 % / Rmerge(I) obs: 1.149 / Mean I/σ(I) obs: 1.3 / Num. unique obs: 8538 / Rsym value: 1.149 / % possible all: 97.3

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
XDSdata reduction
XSCALEdata scaling
PHASERphasing
REFMAC5.8.0155refinement
PDB_EXTRACT3.27data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: none

Resolution: 2.29→92.61 Å / Cor.coef. Fo:Fc: 0.943 / Cor.coef. Fo:Fc free: 0.929 / SU B: 15.274 / SU ML: 0.18 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.264 / ESU R Free: 0.212 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: U VALUES : WITH TLS ADDED HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2525 1962 4.9 %RANDOM
Rwork0.22 ---
obs0.2216 37835 97.78 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 192.81 Å2 / Biso mean: 74.955 Å2 / Biso min: 29.09 Å2
Baniso -1Baniso -2Baniso -3
1--2.47 Å20 Å20.33 Å2
2---2.33 Å2-0 Å2
3---3.88 Å2
Refinement stepCycle: final / Resolution: 2.29→92.61 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4887 0 2 208 5097
Biso mean--54.69 59.57 -
Num. residues----648
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0140.0194745
X-RAY DIFFRACTIONr_bond_other_d0.0030.024255
X-RAY DIFFRACTIONr_angle_refined_deg1.5871.9256485
X-RAY DIFFRACTIONr_angle_other_deg1.28939730
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.0915646
X-RAY DIFFRACTIONr_dihedral_angle_2_deg38.6725.16188
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.49415664
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.9461516
X-RAY DIFFRACTIONr_chiral_restr0.0890.2743
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.0215591
X-RAY DIFFRACTIONr_gen_planes_other0.0030.021049
Refine LS restraints NCS

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

Ens-IDDom-IDAuth asym-IDNumberRms dev position (Å)
11A34160.04
12C34160.04
21B32340.02
22D32340.02
LS refinement shellResolution: 2.29→2.345 Å / Rfactor Rfree error: 0
RfactorNum. reflection% reflection
Rfree0.348 139 -
Rwork0.329 2732 -
obs--96.99 %
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)
16.60951.9616-1.72654.6375-1.16232.6295-0.0484-0.0359-0.00170.09030.03020.1172-0.1117-0.02830.01820.2886-0.00790.03020.3571-0.0130.0075-59.896-26.26116.799
29.72185.91870.96284.83940.00790.5361-0.0368-0.41180.01840.2976-0.1908-0.5146-0.1180.2390.22760.3943-0.0040.01610.6557-0.05310.3582-31.987-13.8810.841
39.52072.497-0.16211.7669-0.26861.0944-0.2006-0.0328-0.5076-0.10740.1848-0.1050.20740.12190.01570.4214-0.0193-0.0040.5923-0.00880.34930.796-1.34411.863
41.5842-0.34850.41741.7685-0.59026.4458-0.0893-0.1587-0.29130.096-0.0181-0.03020.32660.33780.10740.3279-0.00680.08470.41110.05450.0773-56.421-42.38422.251
511.9212-0.17191.68893.94390.59761.1929-0.1443-0.64080.7485-0.3218-0.05360.6404-0.3509-0.3560.19790.470.00010.00350.6453-0.07660.4342-15.644-51.74118.361
612.55191.03180.99690.11630.12330.6660.058-0.3630.617-0.0581-0.05460.12860.0719-0.2624-0.00340.458-0.0187-0.02070.6-0.0950.384212.86-46.5623.259
712.62592.5986-0.2681.7118-0.54851.9063-0.0109-0.68751.01630.0324-0.109-0.255-0.34930.3070.11990.4568-0.04070.030.5018-0.14770.355146.938-38.421.606
84.5352-0.52170.98052.5069-0.97255.8634-0.46230.00491.159-0.25240.1585-0.1957-1.7732-0.3850.30391.340.1719-0.15110.9148-0.04561.0531-23.463-35.70415.115
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A23 - 100
2X-RAY DIFFRACTION2A101 - 141
3X-RAY DIFFRACTION3A142 - 190
4X-RAY DIFFRACTION4B11 - 169
5X-RAY DIFFRACTION5C25 - 100
6X-RAY DIFFRACTION6C101 - 141
7X-RAY DIFFRACTION7C142 - 189
8X-RAY DIFFRACTION8D13 - 168

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