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- PDB-5tru: Structure of the first-in-class checkpoint inhibitor Ipilimumab b... -

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Basic information

Entry
Database: PDB / ID: 5tru
TitleStructure of the first-in-class checkpoint inhibitor Ipilimumab bound to human CTLA-4
Components
  • Cytotoxic T-lymphocyte protein 4
  • Ipilimumab Fab heavy chain
  • Ipilimumab Fab light chain
KeywordsIMMUNE SYSTEM / antibody / complex / Fab
Function / homology
Function and homology information


protein complex involved in cell adhesion / negative regulation of regulatory T cell differentiation / RUNX1 and FOXP3 control the development of regulatory T lymphocytes (Tregs) / clathrin-coated endocytic vesicle / CTLA4 inhibitory signaling / negative regulation of B cell proliferation / negative regulation of T cell proliferation / B cell receptor signaling pathway / T cell receptor signaling pathway / adaptive immune response ...protein complex involved in cell adhesion / negative regulation of regulatory T cell differentiation / RUNX1 and FOXP3 control the development of regulatory T lymphocytes (Tregs) / clathrin-coated endocytic vesicle / CTLA4 inhibitory signaling / negative regulation of B cell proliferation / negative regulation of T cell proliferation / B cell receptor signaling pathway / T cell receptor signaling pathway / adaptive immune response / immune response / positive regulation of apoptotic process / external side of plasma membrane / DNA damage response / perinuclear region of cytoplasm / Golgi apparatus / plasma membrane
Similarity search - Function
Cytotoxic T-lymphocyte antigen 4 / Cytotoxic T-lymphocyte protein 4/CD28 / Immunoglobulin V-Type / Immunoglobulin V-set domain / Immunoglobulin V-set domain / Immunoglobulin subtype / Immunoglobulin / Immunoglobulin-like domain superfamily / Immunoglobulins / Immunoglobulin-like fold ...Cytotoxic T-lymphocyte antigen 4 / Cytotoxic T-lymphocyte protein 4/CD28 / Immunoglobulin V-Type / Immunoglobulin V-set domain / Immunoglobulin V-set domain / Immunoglobulin subtype / Immunoglobulin / Immunoglobulin-like domain superfamily / Immunoglobulins / Immunoglobulin-like fold / Immunoglobulin-like / Sandwich / Mainly Beta
Similarity search - Domain/homology
Cytotoxic T-lymphocyte protein 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3 Å
AuthorsRamagopal, U.A. / Liu, W. / Garrett-Thomson, S.C. / Yan, Q. / Srinivasan, M. / Wong, S.C. / Bell, A. / Mankikar, S. / Rangan, V.S. / Deshpande, S. ...Ramagopal, U.A. / Liu, W. / Garrett-Thomson, S.C. / Yan, Q. / Srinivasan, M. / Wong, S.C. / Bell, A. / Mankikar, S. / Rangan, V.S. / Deshpande, S. / Bonanno, J.B. / Korman, A.J. / Almo, S.C.
CitationJournal: Proc. Natl. Acad. Sci. U.S.A. / Year: 2017
Title: Structural basis for cancer immunotherapy by the first-in-class checkpoint inhibitor ipilimumab.
Authors: Ramagopal, U.A. / Liu, W. / Garrett-Thomson, S.C. / Bonanno, J.B. / Yan, Q. / Srinivasan, M. / Wong, S.C. / Bell, A. / Mankikar, S. / Rangan, V.S. / Deshpande, S. / Korman, A.J. / Almo, S.C.
History
DepositionOct 27, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 10, 2017Provider: repository / Type: Initial release
Revision 1.1May 24, 2017Group: Database references
Revision 1.2Jun 7, 2017Group: Database references
Revision 1.3Oct 4, 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

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
L: Ipilimumab Fab light chain
H: Ipilimumab Fab heavy chain
l: Ipilimumab Fab light chain
h: Ipilimumab Fab heavy chain
c: Cytotoxic T-lymphocyte protein 4
C: Cytotoxic T-lymphocyte protein 4


Theoretical massNumber of molelcules
Total (without water)120,6936
Polymers120,6936
Non-polymers00
Water00
1
L: Ipilimumab Fab light chain
H: Ipilimumab Fab heavy chain
C: Cytotoxic T-lymphocyte protein 4


Theoretical massNumber of molelcules
Total (without water)60,3473
Polymers60,3473
Non-polymers00
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4880 Å2
ΔGint-34 kcal/mol
Surface area24250 Å2
MethodPISA
2
l: Ipilimumab Fab light chain
h: Ipilimumab Fab heavy chain
c: Cytotoxic T-lymphocyte protein 4


Theoretical massNumber of molelcules
Total (without water)60,3473
Polymers60,3473
Non-polymers00
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4980 Å2
ΔGint-37 kcal/mol
Surface area23990 Å2
MethodPISA
Unit cell
Length a, b, c (Å)95.844, 197.502, 148.117
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number20
Space group name H-MC2221

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Components

#1: Antibody Ipilimumab Fab light chain


Mass: 23477.023 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Cricetulus griseus (Chinese hamster)
#2: Antibody Ipilimumab Fab heavy chain


Mass: 24232.135 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Cricetulus griseus (Chinese hamster)
#3: Protein Cytotoxic T-lymphocyte protein 4 / Cytotoxic T-lymphocyte-associated antigen 4 / CTLA-4


Mass: 12637.422 Da / Num. of mol.: 2 / Fragment: UNP residues 37-154
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CTLA4, CD152 / Plasmid: pET3a / Production host: Escherichia coli (E. coli) / Strain (production host): BL21 (DE3) pLysS / References: UniProt: P16410

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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: 2.99 Å3/Da / Density % sol: 58.9 %
Crystal growTemperature: 291 K / Method: vapor diffusion / pH: 7.5
Details: 0.1M ammonium sulfate, 0.1M Tris pH 7.5, 20% PEG 1500

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 24-ID-E / Wavelength: 0.979 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Aug 2, 2009
RadiationMonochromator: Si(220) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 3→34.91 Å / Num. obs: 28514 / % possible obs: 99.7 % / Redundancy: 6.4 % / Rmerge(I) obs: 0.143 / Χ2: 1.208 / Net I/av σ(I): 14.6 / Net I/σ(I): 6.1 / Num. measured all: 181876
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsDiffraction-ID% possible all
3-3.056.60.82199.9
3.05-3.116.50.727199.8
3.11-3.176.60.629199.9
3.17-3.236.50.491199.8
3.23-3.36.50.42199.9
3.3-3.386.60.333199.8
3.38-3.466.50.284199.8
3.46-3.566.50.236199.8
3.56-3.666.60.218199.8
3.66-3.786.50.197199.9
3.78-3.916.40.167199.9
3.91-4.076.40.155199.9
4.07-4.266.40.128199.8
4.26-4.486.30.11199.9
4.48-4.766.20.1021100
4.76-5.136.20.092199.9
5.13-5.646.20.084199.5
5.64-6.466.20.084199.9
6.46-8.136.30.071199.6
8.13-505.70.058197.6

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Processing

Software
NameVersionClassification
SCALEPACKdata scaling
REFMAC5refinement
PDB_EXTRACT3.2data extraction
HKL-2000data reduction
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1I85

1i85


Resolution: 3→34.91 Å / Cor.coef. Fo:Fc: 0.939 / Cor.coef. Fo:Fc free: 0.885 / SU B: 51.86 / SU ML: 0.396 / SU R Cruickshank DPI: 0.368 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R Free: 0.447
Details: HYDROGENS HAVE BEEN USED IF PRESENT IN THE INPUT U VALUES: WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.2677 1447 5.1 %RANDOM
Rwork0.2035 ---
obs0.2067 26945 99.21 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 159.11 Å2 / Biso mean: 69.607 Å2 / Biso min: 44 Å2
Baniso -1Baniso -2Baniso -3
1-3.82 Å20 Å2-0 Å2
2---1.51 Å20 Å2
3----2.3 Å2
Refinement stepCycle: final / Resolution: 3→34.91 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8036 0 0 0 8036
Num. residues----1081
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.028232
X-RAY DIFFRACTIONr_angle_refined_deg1.4611.94711224
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.89951071
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.52823.782312
X-RAY DIFFRACTIONr_dihedral_angle_3_deg19.574151209
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.7611537
X-RAY DIFFRACTIONr_chiral_restr0.0910.21277
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0216219
X-RAY DIFFRACTIONr_mcbond_it0.6082.714313
X-RAY DIFFRACTIONr_mcangle_it1.1044.0625373
X-RAY DIFFRACTIONr_scbond_it0.612.6883919
LS refinement shellResolution: 2.998→3.075 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.39 96 -
Rwork0.349 1953 -
all-2049 -
obs--98.18 %
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)
12.3627-0.8163-1.36521.10370.59421.43520.0871-0.00710.134-0.00370.013-0.22550.08910.1509-0.10010.82570.0109-0.10390.03470.00530.1012-34.2475-24.776210.4836
24.225-1.2152-0.83461.31230.66121.6805-0.056-0.1074-0.33330.1475-0.0290.01220.42440.13320.0850.8828-0.056-0.07360.04070.05810.1289-41.3433-40.415416.9397
32.57980.8107-0.19092.47450.53821.30140.1108-0.1704-0.11970.3310.0809-0.84540.05780.5414-0.19160.84470.0358-0.10.2383-0.02130.3597-28.484811.126159.7547
43.22441.2657-0.55051.96160.27991.54590.14160.06010.03020.04290.0299-0.2418-0.19410.2767-0.17140.74630.01980.00850.0846-0.03780.2303-36.821427.708559.0292
52.86971.05633.22232.99512.16297.302-0.03770.00880.1584-0.0539-0.07670.4184-0.2158-0.90380.11440.62990.03640.07820.4431-0.02190.5836-72.89729.40551.8617
62.7329-1.5368-1.26812.75333.03928.1849-0.156-0.03120.19030.0674-0.12550.53230.2289-0.75410.28150.673-0.09-0.06490.36460.05270.567-75.0721-19.559730.0478
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1L1 - 213
2X-RAY DIFFRACTION2H1 - 220
3X-RAY DIFFRACTION3l1 - 212
4X-RAY DIFFRACTION4h1 - 218
5X-RAY DIFFRACTION5c2 - 118
6X-RAY DIFFRACTION6C2 - 117

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