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- PDB-6t3j: Dual Epitope Targeting by Anti-DR5 Antibodies -

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Basic information

Entry
Database: PDB / ID: 6t3j
TitleDual Epitope Targeting by Anti-DR5 Antibodies
Components
  • IgG1-hDR5-01-Heavy Chain
  • IgG1-hDR5-01-Light Chain
  • IgG1-hDR5-05-Heavy Chain
  • IgG1-hDR5-05-Light Chain
  • Tumor necrosis factor receptor superfamily member 10B
KeywordsAPOPTOSIS / DR5 / ANTIBODY
Function / homology
Function and homology information


TRAIL receptor activity / TRAIL binding / TRAIL signaling / TRAIL-activated apoptotic signaling pathway / Regulation by c-FLIP / CASP8 activity is inhibited / Dimerization of procaspase-8 / Caspase activation via Death Receptors in the presence of ligand / activation of NF-kappaB-inducing kinase activity / defense response to tumor cell ...TRAIL receptor activity / TRAIL binding / TRAIL signaling / TRAIL-activated apoptotic signaling pathway / Regulation by c-FLIP / CASP8 activity is inhibited / Dimerization of procaspase-8 / Caspase activation via Death Receptors in the presence of ligand / activation of NF-kappaB-inducing kinase activity / defense response to tumor cell / TP53 Regulates Transcription of Death Receptors and Ligands / RIPK1-mediated regulated necrosis / extrinsic apoptotic signaling pathway via death domain receptors / intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress / response to endoplasmic reticulum stress / Cell surface interactions at the vascular wall / cellular response to mechanical stimulus / signaling receptor activity / regulation of apoptotic process / positive regulation of canonical NF-kappaB signal transduction / cell surface receptor signaling pathway / positive regulation of apoptotic process / apoptotic process / cell surface / plasma membrane
Similarity search - Function
Tumour necrosis factor receptor 10 / Tumor necrosis factor receptor 10, N-terminal / Tumour necrosis factor receptor 10A/B, death domain / 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 / Death domain profile. / DEATH domain, found in proteins involved in cell death (apoptosis). ...Tumour necrosis factor receptor 10 / Tumor necrosis factor receptor 10, N-terminal / Tumour necrosis factor receptor 10A/B, death domain / 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 / Death domain profile. / DEATH domain, found in proteins involved in cell death (apoptosis). / Death domain / Death domain / Death-like domain superfamily
Similarity search - Domain/homology
Tumor necrosis factor receptor superfamily member 10B
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.05 Å
AuthorsTauchert, M.J. / Augustin, M. / Krapp, S. / Overdijk, M.B. / Breij, E.C.W. / Hibbert, R.G.
CitationJournal: Mol.Cancer Ther. / Year: 2020
Title: Dual Epitope Targeting and Enhanced Hexamerization by DR5 Antibodies as a Novel Approach to Induce Potent Antitumor Activity Through DR5 Agonism.
Authors: Overdijk, M.B. / Strumane, K. / Beurskens, F.J. / Ortiz Buijsse, A. / Vermot-Desroches, C. / Vuillermoz, B.S. / Kroes, T. / de Jong, B. / Hoevenaars, N. / Hibbert, R.G. / Lingnau, A. / ...Authors: Overdijk, M.B. / Strumane, K. / Beurskens, F.J. / Ortiz Buijsse, A. / Vermot-Desroches, C. / Vuillermoz, B.S. / Kroes, T. / de Jong, B. / Hoevenaars, N. / Hibbert, R.G. / Lingnau, A. / Forssmann, U. / Schuurman, J. / Parren, P.W.H.I. / de Jong, R.N. / Breij, E.C.W.
History
DepositionOct 11, 2019Deposition site: PDBE / Processing site: PDBE
Revision 1.0Sep 16, 2020Provider: repository / Type: Initial release
Revision 1.1Oct 14, 2020Group: 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 / _citation_author.name

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: IgG1-hDR5-01-Heavy Chain
B: IgG1-hDR5-01-Light Chain
C: IgG1-hDR5-05-Heavy Chain
D: IgG1-hDR5-05-Light Chain
E: Tumor necrosis factor receptor superfamily member 10B
F: IgG1-hDR5-01-Heavy Chain
G: IgG1-hDR5-01-Light Chain
H: IgG1-hDR5-05-Heavy Chain
I: IgG1-hDR5-05-Light Chain
J: Tumor necrosis factor receptor superfamily member 10B


Theoretical massNumber of molelcules
Total (without water)223,38410
Polymers223,38410
Non-polymers00
Water00
1
A: IgG1-hDR5-01-Heavy Chain
B: IgG1-hDR5-01-Light Chain
C: IgG1-hDR5-05-Heavy Chain
D: IgG1-hDR5-05-Light Chain
E: Tumor necrosis factor receptor superfamily member 10B


Theoretical massNumber of molelcules
Total (without water)111,6925
Polymers111,6925
Non-polymers00
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
F: IgG1-hDR5-01-Heavy Chain
G: IgG1-hDR5-01-Light Chain
H: IgG1-hDR5-05-Heavy Chain
I: IgG1-hDR5-05-Light Chain
J: Tumor necrosis factor receptor superfamily member 10B


Theoretical massNumber of molelcules
Total (without water)111,6925
Polymers111,6925
Non-polymers00
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)121.604, 90.926, 138.379
Angle α, β, γ (deg.)90.000, 103.790, 90.000
Int Tables number4
Space group name H-MP1211
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21C
12A
22F
13A
23H
14B
24D
15B
25G
16B
26I
17C
27F
18C
28H
19D
29G
110D
210I
111E
211J
112F
212H
113G
213I

NCS domain segments:
Dom-IDComponent-IDEns-IDRefine codeAuth asym-IDAuth seq-ID
1010A1 - 219
2010C1 - 219
1020A1 - 219
2020F1 - 219
1030A2 - 218
2030H2 - 218
1040B1 - 211
2040D1 - 210
1050B1 - 211
2050G1 - 211
1060B1 - 211
2060I1 - 210
1070C1 - 219
2070F1 - 219
1080C2 - 218
2080H2 - 218
1090D1 - 209
2090G1 - 210
10100D1 - 210
20100I1 - 210
10110E74 - 182
20110J74 - 182
10120F2 - 218
20120H2 - 218
10130G1 - 210
20130I1 - 209

NCS ensembles :
ID
1
2
3
4
5
6
7
8
9
10
11
12
13

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Components

#1: Antibody IgG1-hDR5-01-Heavy Chain


Mass: 25099.020 Da / Num. of mol.: 2 / Fragment: >#FRAGMENT#< / Mutation: G56T
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Cell line (production host): HEK293F / Production host: Homo sapiens (human)
#2: Antibody IgG1-hDR5-01-Light Chain


Mass: 23436.033 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Cell line (production host): HEK293F / Production host: Homo sapiens (human)
#3: Antibody IgG1-hDR5-05-Heavy Chain


Mass: 25108.066 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Cell line (production host): HEK293F / Production host: Homo sapiens (human)
#4: Antibody IgG1-hDR5-05-Light Chain


Mass: 23385.734 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Cell line: HEK293F / Cell line (production host): HEK293F / Production host: Homo sapiens (human)
#5: Protein Tumor necrosis factor receptor superfamily member 10B / Death receptor 5 / TNF-related apoptosis-inducing ligand receptor 2 / TRAIL-R2


Mass: 14663.296 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human)
Gene: TNFRSF10B, DR5, KILLER, TRAILR2, TRICK2, ZTNFR9, UNQ160/PRO186
Cell line (production host): HEK293F / Production host: Homo sapiens (human) / References: UniProt: O14763
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: 3.4 Å3/Da / Density % sol: 63.82 %
Crystal growTemperature: 281 K / Method: vapor diffusion, hanging drop / pH: 4.6
Details: 10% (w/v) PEG 4000 200 mM ammonium sulphate 100 mM Sodium acetate pH 4.6

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 1.00001 Å
DetectorType: DECTRIS PILATUS3 S 6M / Detector: PIXEL / Date: Feb 27, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.00001 Å / Relative weight: 1
ReflectionResolution: 3.05→134.41 Å / Num. obs: 55388 / % possible obs: 98.5 % / Redundancy: 3 % / Biso Wilson estimate: 79.206 Å2 / CC1/2: 0.997 / Rmerge(I) obs: 0.088 / Rrim(I) all: 0.107 / Χ2: 1.057 / Net I/σ(I): 10.69
Reflection shellResolution: 3.05→3.3 Å / Redundancy: 3.1 % / Rmerge(I) obs: 0.82 / Mean I/σ(I) obs: 1.77 / Num. unique obs: 11644 / CC1/2: 0.998 / Rrim(I) all: 0.024 / % possible all: 99

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Processing

Software
NameVersionClassification
REFMAC5.8.0049refinement
XSCALEdata scaling
PDB_EXTRACT3.25data extraction
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 3.05→134.41 Å / Cor.coef. Fo:Fc: 0.918 / Cor.coef. Fo:Fc free: 0.907 / SU B: 63.398 / SU ML: 0.482 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R Free: 0.447
Details: U VALUES : WITH TLS ADDED HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2819 534 1 %RANDOM
Rwork0.2505 ---
obs0.2508 54854 98.51 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 691.7 Å2 / Biso mean: 134.398 Å2 / Biso min: 40.63 Å2
Baniso -1Baniso -2Baniso -3
1-2 Å2-0 Å20.27 Å2
2---2.22 Å20 Å2
3---0.08 Å2
Refinement stepCycle: final / Resolution: 3.05→134.41 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms14837 0 0 0 14837
Num. residues----1942
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.01914932
X-RAY DIFFRACTIONr_bond_other_d0.0040.0213336
X-RAY DIFFRACTIONr_angle_refined_deg1.3411.94320376
X-RAY DIFFRACTIONr_angle_other_deg1.147330820
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.3551932
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.96924.485573
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.687152265
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.8971550
X-RAY DIFFRACTIONr_chiral_restr0.070.22288
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.02117086
X-RAY DIFFRACTIONr_gen_planes_other0.0030.023324
Refine LS restraints NCS

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

Ens-IDDom-IDAuth asym-IDNumberRms dev position (Å)
11A56930.1
12C56930.1
21A62060.1
22F62060.1
31A57460.1
32H57460.1
41B51780.12
42D51780.12
51B62240.09
52G62240.09
61B52640.12
62I52640.12
71C55020.12
72F55020.12
81C64340.06
82H64340.06
91D49170.13
92G49170.13
101D62000.07
102I62000.07
111E29300.12
112J29300.12
121F54040.12
122H54040.12
131G50330.12
132I50330.12
LS refinement shellResolution: 3.05→3.129 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.483 30 -
Rwork0.403 4031 -
all-4061 -
obs--97.9 %
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)
13.008-1.57681.58831.7562-0.25825.88870.20410.5730.2227-0.7693-0.236-0.5074-0.03320.04370.03190.5019-0.02030.31990.15780.03480.788310.365-13.65642.746
22.2125-1.22380.40836.3071.37754.9796-0.05460.52580.3571-0.9628-0.0775-0.0843-0.25260.25740.13210.6966-0.0840.21740.65210.00310.71310.94511.17419.098
31.5677-2.73820.7717.2634-2.04351.7925-0.1467-0.1116-0.1276-0.14250.1256-0.0270.0018-0.36530.02110.08660.01810.10940.2236-0.02990.5107-3.898-0.91453.915
41.4444-0.1104-0.89632.04352.25047.1934-0.00940.7586-0.1591-0.7772-0.17220.33960.324-0.59890.18150.6780.09350.00890.6761-0.05140.7265-14.8379.07420.438
53.65261.05940.2386.13213.09743.10310.0556-0.31020.2984-0.20040.0172-0.5391-0.60070.4658-0.07270.2795-0.1270.08460.4289-0.02980.7962-4.434-0.6193.646
63.58942.99480.55143.18290.16513.69580.0008-0.7425-0.41870.7444-0.2103-0.4256-0.1748-0.3350.20950.99640.1448-0.0780.9074-0.10581.2685-10.20711.136127.712
74.1704-1.9374-0.27875.41170.82484.77650.0227-0.52380.3560.3608-0.26930.6138-0.3352-0.36560.24670.1725-0.08890.09290.2493-0.12730.7035-25.984-3.89996.92
86.1213.250.49762.98870.70352.7795-0.1179-0.25131.22910.45490.11630.0098-0.62440.06470.00171.02810.08870.07960.7497-0.22431.2756-22.06520.878123.374
96.63282.2343-2.99591.0385-0.68042.39670.1628-0.06730.17150.1365-0.0228-0.1843-0.18940.2782-0.140.22250.002-0.01680.16860.05220.79855.544-19.99673.563
104.2828-0.7722-2.96440.7342-0.44216.24890.45150.6278-0.1947-0.539-0.19520.166700.2226-0.25630.47720.0435-0.04190.2111-0.04150.776218.81850.642.2
110.92870.3709-1.57255.99820.39232.9767-0.09590.3788-0.2578-1.5981-0.12820.59270.079-0.50240.22411.05570.2652-0.33611.1434-0.26081.373630.0627.34517.082
122.9478-2.2899-1.05037.46980.93562.05620.0244-0.0237-0.06780.1241-0.0132-0.02190.15140.4452-0.01130.01980.03410.02080.2536-0.04210.587632.33536.9353.289
131.08521.15620.04113.1431-3.21827.4746-0.22490.7924-0.0837-0.7560.0122-0.3919-0.22940.92630.21270.86690.42110.09041.1649-0.10890.971345.39729.15319.662
141.27242.1743-1.16814.081-2.37341.61710.3251-0.2133-0.0570.0865-0.0510.6360.5621-0.2165-0.27411.8861-0.18550.16281.17390.5162.686730.34738.06996.924
150.0204-0.0024-0.01320.0015-0.00070.0219-0.101-0.0581-0.16990.00520.06080.00930.2022-0.07850.04032.2473-0.1933-0.34952.61720.12522.428534.95528.572131.662
166.2403-3.84731.48669.985-3.50542.9485-0.0905-0.694-0.70010.9802-0.15190.48620.32770.29310.24230.79730.16460.13630.81840.20951.351151.98640.827100.351
170.04610.08-0.03150.3969-0.17080.1060.1595-0.22850.1099-0.032-0.22430.3289-0.08930.07180.06472.2173-0.13190.14472.0850.1782.144646.56518.143128.446
187.06582.57233.371.47171.09093.50140.06990.1972-0.33840.0920.0455-0.03770.05820.0472-0.11550.19520.04190.17610.1165-0.00040.743423.06356.03373.993
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A1 - 119
2X-RAY DIFFRACTION2A120 - 219
3X-RAY DIFFRACTION3B1 - 108
4X-RAY DIFFRACTION4B109 - 212
5X-RAY DIFFRACTION5C1 - 117
6X-RAY DIFFRACTION6C118 - 219
7X-RAY DIFFRACTION7D1 - 106
8X-RAY DIFFRACTION8D107 - 210
9X-RAY DIFFRACTION9E73 - 184
10X-RAY DIFFRACTION10F1 - 119
11X-RAY DIFFRACTION11F120 - 219
12X-RAY DIFFRACTION12G1 - 108
13X-RAY DIFFRACTION13G109 - 213
14X-RAY DIFFRACTION14H2 - 117
15X-RAY DIFFRACTION15H118 - 219
16X-RAY DIFFRACTION16I1 - 106
17X-RAY DIFFRACTION17I107 - 210
18X-RAY DIFFRACTION18J74 - 183

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