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- PDB-7su0: Crystal structure of an acidic pH-selective Ipilimumab variant Ip... -

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Basic information

Entry
Database: PDB / ID: 7su0
TitleCrystal structure of an acidic pH-selective Ipilimumab variant Ipi.105 in complex with CTLA-4
Components
  • Cytotoxic T-lymphocyte protein 4
  • Fab heavy chain
  • Fab light chain
KeywordsIMMUNE SYSTEM / Immunoglobulin / checkpoint / antibody / complex
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 / Co-stimulation by CD28 / Co-inhibition by CTLA4 / negative regulation of B cell proliferation / negative regulation of T cell proliferation / B cell receptor signaling pathway / T cell receptor signaling pathway ...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 / Co-stimulation by CD28 / Co-inhibition by CTLA4 / 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 / Immunoglobulin-like fold / Immunoglobulins ...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 / Immunoglobulin-like fold / Immunoglobulins / Immunoglobulin-like / Sandwich / Mainly Beta
Similarity search - Domain/homology
CITRATE ANION / DI(HYDROXYETHYL)ETHER / Cytotoxic T-lymphocyte protein 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.41 Å
AuthorsLee, P.S. / Chau, B. / Strop, P.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Mabs / Year: 2022
Title: Improved therapeutic index of an acidic pH-selective antibody.
Authors: Lee, P.S. / MacDonald, K.G. / Massi, E. / Chew, P.V. / Bee, C. / Perkins, P. / Chau, B. / Thudium, K. / Lohre, J. / Nandi, P. / Deyanova, E.G. / Barman, I. / Gudmundsson, O. / Dollinger, G. ...Authors: Lee, P.S. / MacDonald, K.G. / Massi, E. / Chew, P.V. / Bee, C. / Perkins, P. / Chau, B. / Thudium, K. / Lohre, J. / Nandi, P. / Deyanova, E.G. / Barman, I. / Gudmundsson, O. / Dollinger, G. / Sproul, T. / Engelhardt, J.J. / Strop, P. / Rajpal, A.
History
DepositionNov 15, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 2, 2022Provider: repository / Type: Initial release
Revision 1.1Oct 18, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.2Oct 16, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
C: Cytotoxic T-lymphocyte protein 4
H: Fab heavy chain
L: Fab light chain
D: Cytotoxic T-lymphocyte protein 4
I: Fab heavy chain
M: Fab light chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)124,62311
Polymers123,6646
Non-polymers9595
Water64936
1
C: Cytotoxic T-lymphocyte protein 4
H: Fab heavy chain
L: Fab light chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)62,2755
Polymers61,8323
Non-polymers4422
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
D: Cytotoxic T-lymphocyte protein 4
I: Fab heavy chain
M: Fab light chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)62,3496
Polymers61,8323
Non-polymers5163
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)96.730, 197.840, 146.490
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number20
Space group name H-MC2221
Space group name HallC2c2
Symmetry operation#1: x,y,z
#2: x,-y,-z
#3: -x,y,-z+1/2
#4: -x,-y,z+1/2
#5: x+1/2,y+1/2,z
#6: x+1/2,-y+1/2,-z
#7: -x+1/2,y+1/2,-z+1/2
#8: -x+1/2,-y+1/2,z+1/2
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
d_1ens_1(chain "C" and (resid 2 through 117 or resid 301))
d_2ens_1chain "D"
d_1ens_2(chain "H" and (resid 1 through 126 or resid 135 through 213))
d_2ens_2chain "I"
d_1ens_3(chain "L" and resid 1 through 211)
d_2ens_3chain "M"

NCS domain segments:
Dom-IDComponent-IDEns-IDBeg label comp-IDEnd label comp-IDLabel asym-IDLabel seq-ID
d_11ens_1ALAILEA1 - 116
d_12ens_1NAGNAGC
d_21ens_1ALAILEF1 - 116
d_22ens_1NAGNAGG
d_11ens_2PCAPROD1 - 131
d_12ens_2THRPROD134 - 212
d_21ens_2PCAPROH1 - 210
d_11ens_3GLUARGE1 - 212
d_21ens_3GLUARGI1 - 212

NCS ensembles :
ID
ens_1
ens_2
ens_3

NCS oper:
IDCodeMatrixVector
1given(-0.959078532931, 0.10381847345, 0.263419992108), (0.0567846603886, 0.981976921978, -0.180268763371), (-0.277387580862, -0.157933686316, -0.947688282459)87.1807049816, 14.0851121663, 9.89361751318
2given(-0.945467974283, 0.0305588847245, 0.324278374501), (-0.0310452767194, 0.982601592902, -0.183112807907), (-0.324232170517, -0.183194607428, -0.928069628536)83.0770126658, 16.590979599, 10.5404178171
3given(-0.940685687045, 0.0378073413365, 0.337166195117), (-0.0169036041504, 0.987315067185, -0.157870916499), (-0.338857944212, -0.154206235446, -0.928114071973)82.8618387813, 15.8455318278, 12.5242160078

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Components

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Antibody , 2 types, 4 molecules HILM

#2: Antibody Fab heavy chain


Mass: 24749.684 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human)
#3: Antibody Fab light chain


Mass: 23527.035 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human)

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Protein / Sugars , 2 types, 5 molecules CD

#1: Protein Cytotoxic T-lymphocyte protein 4 / Cytotoxic T-lymphocyte-associated antigen 4 / CTLA-4


Mass: 13555.421 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CTLA4, CD152 / Production host: Homo sapiens (human) / References: UniProt: P16410
#4: Sugar ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C8H15NO6
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0

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Non-polymers , 3 types, 38 molecules

#5: Chemical ChemComp-FLC / CITRATE ANION


Mass: 189.100 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C6H5O7
#6: Chemical ChemComp-PEG / DI(HYDROXYETHYL)ETHER


Mass: 106.120 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C4H10O3
#7: 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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Details

Has ligand of interestN
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: 2.83 Å3/Da / Density % sol: 56.59 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop
Details: 0.2 M ammonium citrate dibasic, 20% w/v PEG 1,000, pH 5.2

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS EIGER2 X 9M / Detector: PIXEL / Date: Feb 26, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.405→50 Å / Num. obs: 38346 / % possible obs: 90.6 % / Redundancy: 6.7 % / Biso Wilson estimate: 48.27 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.096 / Rpim(I) all: 0.04 / Net I/σ(I): 14.4
Reflection shellResolution: 2.405→2.557 Å / Rmerge(I) obs: 1.487 / Mean I/σ(I) obs: 1.6 / Num. unique obs: 1918 / CC1/2: 0.577 / Rpim(I) all: 0.61 / % possible all: 96.1

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Processing

Software
NameVersionClassification
PHENIX1.19.2_4158refinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5TRU, 4NM4, 3OSK

5tru

4nm4

3osk


Resolution: 2.41→36.36 Å / SU ML: 0.3274 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 33.4955
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2638 1906 4.98 %
Rwork0.2062 36398 -
obs0.209 38304 69.89 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 45.5 Å2
Refinement stepCycle: LAST / Resolution: 2.41→36.36 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8249 0 62 36 8347
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00978501
X-RAY DIFFRACTIONf_angle_d1.343311569
X-RAY DIFFRACTIONf_chiral_restr0.06631312
X-RAY DIFFRACTIONf_plane_restr0.02151481
X-RAY DIFFRACTIONf_dihedral_angle_d9.70151204
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDRefine-IDTypeRms dev position (Å)
ens_1d_2CX-RAY DIFFRACTIONTorsion NCS3.19691385703
ens_2d_2HX-RAY DIFFRACTIONTorsion NCS0.731513403627
ens_3d_2IX-RAY DIFFRACTIONTorsion NCS0.960121446233
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.41-2.470.4964290.4615475X-RAY DIFFRACTION13.13
2.47-2.530.4735440.3789926X-RAY DIFFRACTION25.13
2.53-2.610.3747750.34711375X-RAY DIFFRACTION37.4
2.61-2.630.3725210.4025506X-RAY DIFFRACTION50.05
2.71-2.790.38331050.31141994X-RAY DIFFRACTION68.3
2.79-2.90.33861370.29962793X-RAY DIFFRACTION75.21
2.9-3.030.30081490.29653018X-RAY DIFFRACTION81.52
3.03-3.190.35061770.29523327X-RAY DIFFRACTION89.96
3.19-3.390.33921880.2683591X-RAY DIFFRACTION97.25
3.39-3.650.28532130.22063682X-RAY DIFFRACTION99.46
3.65-4.020.30121870.20283262X-RAY DIFFRACTION87.6
4.02-4.60.21111960.14393761X-RAY DIFFRACTION99.97
4.6-5.790.17612060.14243757X-RAY DIFFRACTION99.97
5.79-36.360.22391790.17273931X-RAY DIFFRACTION99.76
Refinement TLS params.Method: refined / Origin x: 45.3493160417 Å / Origin y: -23.6126549032 Å / Origin z: 0.60171841117 Å
111213212223313233
T0.199538310487 Å2-0.00281393785726 Å2-0.0361722988326 Å2-0.108402095026 Å2-0.0192210288364 Å2--0.171914069128 Å2
L0.37339747129 °20.0532447416683 °20.0390432850761 °2-0.372367331518 °2-0.176155073814 °2--0.584465617523 °2
S0.0682511915062 Å °0.0272628377567 Å °-0.0446329926338 Å °-0.025893257085 Å °-0.00437294269059 Å °0.106712394273 Å °0.0738436373373 Å °-0.103019804231 Å °-0.0650642887854 Å °
Refinement TLS groupSelection details: all

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