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- PDB-6uj9: Crystal structure of HLA-B*07:02 with R140Q mutant IDH2 peptide i... -

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Basic information

Entry
Database: PDB / ID: 6uj9
TitleCrystal structure of HLA-B*07:02 with R140Q mutant IDH2 peptide in complex with Fab
Components
  • Beta-2-microglobulin
  • Fab heavy chain
  • Fab light chain
  • HLA class I histocompatibility antigen, B-7 alpha chain
  • Isocitrate dehydrogenase [NADP], mitochondrial
KeywordsIMMUNE SYSTEM / HLA-B7 / MHC-I / immunotherapy / IDH2
Function / homology
Function and homology information


Citric acid cycle (TCA cycle) / Maturation of TCA enzymes and regulation of TCA cycle / isocitrate metabolic process / isocitrate dehydrogenase (NADP+) / isocitrate dehydrogenase (NADP+) activity / NADP+ metabolic process / 2-oxoglutarate metabolic process / glyoxylate cycle / regulation of interleukin-12 production / regulation of dendritic cell differentiation ...Citric acid cycle (TCA cycle) / Maturation of TCA enzymes and regulation of TCA cycle / isocitrate metabolic process / isocitrate dehydrogenase (NADP+) / isocitrate dehydrogenase (NADP+) activity / NADP+ metabolic process / 2-oxoglutarate metabolic process / glyoxylate cycle / regulation of interleukin-12 production / regulation of dendritic cell differentiation / regulation of T cell anergy / regulation of interleukin-6 production / TAP binding / protection from natural killer cell mediated cytotoxicity / antigen processing and presentation of endogenous peptide antigen via MHC class I via ER pathway, TAP-independent / antigen processing and presentation of endogenous peptide antigen via MHC class Ib / detection of bacterium / tricarboxylic acid cycle / Mitochondrial protein degradation / : / : / secretory granule membrane / positive regulation of receptor binding / early endosome lumen / Nef mediated downregulation of MHC class I complex cell surface expression / negative regulation of receptor binding / DAP12 interactions / cellular response to iron ion / lumenal side of endoplasmic reticulum membrane / Endosomal/Vacuolar pathway / Antigen Presentation: Folding, assembly and peptide loading of class I MHC / peptide antigen assembly with MHC class II protein complex / cellular response to iron(III) ion / antigen processing and presentation of exogenous protein antigen via MHC class Ib, TAP-dependent / MHC class II protein complex / negative regulation of forebrain neuron differentiation / ER to Golgi transport vesicle membrane / peptide antigen assembly with MHC class I protein complex / regulation of erythrocyte differentiation / Transcriptional activation of mitochondrial biogenesis / regulation of iron ion transport / MHC class I peptide loading complex / response to molecule of bacterial origin / defense response / HFE-transferrin receptor complex / T cell mediated cytotoxicity / antigen processing and presentation of endogenous peptide antigen via MHC class I / positive regulation of T cell cytokine production / antigen processing and presentation of exogenous peptide antigen via MHC class II / MHC class I protein complex / positive regulation of immune response / peptide antigen binding / negative regulation of neurogenesis / positive regulation of T cell mediated cytotoxicity / positive regulation of receptor-mediated endocytosis / multicellular organismal-level iron ion homeostasis / positive regulation of T cell activation / cellular response to nicotine / specific granule lumen / recycling endosome membrane / phagocytic vesicle membrane / positive regulation of cellular senescence / NAD binding / Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell / negative regulation of epithelial cell proliferation / Interferon gamma signaling / Interferon alpha/beta signaling / MHC class II protein complex binding / positive regulation of protein binding / Modulation by Mtb of host immune system / late endosome membrane / sensory perception of smell / tertiary granule lumen / peroxisome / DAP12 signaling / protein-folding chaperone binding / negative regulation of neuron projection development / iron ion transport / T cell differentiation in thymus / ER-Phagosome pathway / protein refolding / early endosome membrane / protein homotetramerization / adaptive immune response / amyloid fibril formation / carbohydrate metabolic process / intracellular iron ion homeostasis / learning or memory / immune response / mitochondrial matrix / Amyloid fiber formation / endoplasmic reticulum lumen / Golgi membrane / external side of plasma membrane / signaling receptor binding / lysosomal membrane / innate immune response / focal adhesion / Neutrophil degranulation / SARS-CoV-2 activates/modulates innate and adaptive immune responses
Similarity search - Function
Isocitrate dehydrogenase NADP-dependent / Isocitrate/isopropylmalate dehydrogenase, conserved site / Isocitrate and isopropylmalate dehydrogenases signature. / Isopropylmalate dehydrogenase-like domain / Isocitrate/isopropylmalate dehydrogenase / Isocitrate/isopropylmalate dehydrogenase / MHC class I, alpha chain, C-terminal / MHC_I C-terminus / MHC class I alpha chain, alpha1 alpha2 domains / Class I Histocompatibility antigen, domains alpha 1 and 2 ...Isocitrate dehydrogenase NADP-dependent / Isocitrate/isopropylmalate dehydrogenase, conserved site / Isocitrate and isopropylmalate dehydrogenases signature. / Isopropylmalate dehydrogenase-like domain / Isocitrate/isopropylmalate dehydrogenase / Isocitrate/isopropylmalate dehydrogenase / MHC class I, alpha chain, C-terminal / MHC_I C-terminus / MHC class I alpha chain, alpha1 alpha2 domains / Class I Histocompatibility antigen, domains alpha 1 and 2 / Beta-2-Microglobulin / : / MHC class I-like antigen recognition-like / MHC class I-like antigen recognition-like superfamily / MHC classes I/II-like antigen recognition protein / : / Immunoglobulin/major histocompatibility complex, conserved site / Immunoglobulins and major histocompatibility complex proteins signature. / Immunoglobulin C-Type / Immunoglobulin C1-set / Immunoglobulin C1-set domain / Ig-like domain profile. / Immunoglobulin-like domain / Immunoglobulin-like domain superfamily / Immunoglobulin-like fold / Immunoglobulins / Immunoglobulin-like / Sandwich / Mainly Beta
Similarity search - Domain/homology
DI(HYDROXYETHYL)ETHER / HLA class I histocompatibility antigen, B alpha chain / Isocitrate dehydrogenase [NADP], mitochondrial / Beta-2-microglobulin
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.9 Å
AuthorsMiller, M.S. / Thirawatananond, P. / Aytenfisu, T.Y. / Wright, K. / Gabelli, S.B.
Funding support United States, 3items
OrganizationGrant numberCountry
Department of Defense (DOD, United States)CDMRP BC151831 United States
National Institutes of Health/National Cancer Institute (NIH/NCI)CA062924 United States
National Institutes of Health/National Cancer Institute (NIH/NCI)P30 CA006973 United States
CitationJournal: Nat Commun / Year: 2021
Title: Structural engineering of chimeric antigen receptors targeting HLA-restricted neoantigens.
Authors: Hwang, M.S. / Miller, M.S. / Thirawatananond, P. / Douglass, J. / Wright, K.M. / Hsiue, E.H. / Mog, B.J. / Aytenfisu, T.Y. / Murphy, M.B. / Aitana Azurmendi, P. / Skora, A.D. / Pearlman, A.H. ...Authors: Hwang, M.S. / Miller, M.S. / Thirawatananond, P. / Douglass, J. / Wright, K.M. / Hsiue, E.H. / Mog, B.J. / Aytenfisu, T.Y. / Murphy, M.B. / Aitana Azurmendi, P. / Skora, A.D. / Pearlman, A.H. / Paul, S. / DiNapoli, S.R. / Konig, M.F. / Bettegowda, C. / Pardoll, D.M. / Papadopoulos, N. / Kinzler, K.W. / Vogelstein, B. / Zhou, S. / Gabelli, S.B.
History
DepositionOct 2, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 5, 2021Provider: repository / Type: Initial release
Revision 1.1Nov 17, 2021Group: Database references / Category: citation / citation_author / database_2
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.2Oct 11, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.3Nov 6, 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
A: HLA class I histocompatibility antigen, B-7 alpha chain
B: Beta-2-microglobulin
C: Isocitrate dehydrogenase [NADP], mitochondrial
L: Fab light chain
H: Fab heavy chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)97,76720
Polymers96,1555
Non-polymers1,61315
Water362
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area13810 Å2
ΔGint-128 kcal/mol
Surface area36410 Å2
MethodPISA
Unit cell
Length a, b, c (Å)83.605, 42.006, 125.180
Angle α, β, γ (deg.)90.000, 92.750, 90.000
Int Tables number4
Space group name H-MP1211

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Components

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Protein , 2 types, 2 molecules AB

#1: Protein HLA class I histocompatibility antigen, B-7 alpha chain / MHC class I antigen B*7


Mass: 34609.031 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HLA-B, HLAB / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3) / References: UniProt: P01889
#2: Protein Beta-2-microglobulin


Mass: 13732.547 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: B2M, CDABP0092, HDCMA22P / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3) / References: UniProt: P61769

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Protein/peptide , 1 types, 1 molecules C

#3: Protein/peptide Isocitrate dehydrogenase [NADP], mitochondrial / IDH / ICD-M / IDP / NADP(+)-specific ICDH / Oxalosuccinate decarboxylase


Mass: 1056.171 Da / Num. of mol.: 1 / Mutation: R140Q / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human)
References: UniProt: P48735, isocitrate dehydrogenase (NADP+)

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Antibody , 2 types, 2 molecules LH

#4: Antibody Fab light chain


Mass: 23449.023 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human)
#5: Antibody Fab heavy chain


Mass: 23308.109 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human)

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Non-polymers , 4 types, 17 molecules

#6: Chemical
ChemComp-PEG / DI(HYDROXYETHYL)ETHER


Mass: 106.120 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C4H10O3
#7: Chemical ChemComp-NHE / 2-[N-CYCLOHEXYLAMINO]ETHANE SULFONIC ACID / N-CYCLOHEXYLTAURINE / CHES


Mass: 207.290 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C8H17NO3S / Comment: pH buffer*YM
#8: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: SO4
#9: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 2 / 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: 2.28 Å3/Da / Density % sol: 46.13 %
Crystal growTemperature: 292 K / Method: vapor diffusion, hanging drop / pH: 9.5 / Details: 0.1 M CHES, 20% PEG8000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: NSLS-II / Beamline: 17-ID-1 / Wavelength: 0.9201 Å
DetectorType: DECTRIS EIGER2 X 9M / Detector: PIXEL / Date: Aug 15, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9201 Å / Relative weight: 1
ReflectionResolution: 2.9→48.93 Å / Num. obs: 19451 / % possible obs: 98.1 % / Redundancy: 3.104 % / Biso Wilson estimate: 34.323 Å2 / CC1/2: 0.98 / Rmerge(I) obs: 0.15 / Rrim(I) all: 0.18 / Χ2: 0.893 / Net I/σ(I): 6.48 / Num. measured all: 60383 / Scaling rejects: 4
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured obsNum. possibleNum. unique obsCC1/2Rrim(I) all% possible all
2.9-2.982.9540.5612.034154145914060.7110.67896.4
2.98-3.062.9320.5032.224017138913700.7630.6198.6
3.06-3.153.1850.4042.934360137713690.850.48399.4
3.15-3.243.250.3263.564342134513360.8940.38999.3
3.24-3.353.2230.2834.134119128912780.9080.33899.1
3.35-3.473.2240.2135.084024125912480.9550.25599.1
3.47-3.63.2090.1985.53812120011880.9580.23799
3.6-3.753.2130.1656.293688116211480.970.19798.8
3.75-3.913.2020.1466.923529111111020.9760.17599.2
3.91-4.13.1630.137.783378108010680.9740.15698.9
4.1-4.323.0870.1019.143136102910160.9860.12298.7
4.32-4.593.0220.0959.8528569669450.9830.11697.8
4.59-4.92.9680.0959.926189078820.9850.11697.2
4.9-5.32.660.0959.322378678410.9820.11597
5.3-5.83.0440.1068.922957747540.9850.12997.4
5.8-6.492.9310.1148.420437206970.9710.13896.8
6.49-7.493.2960.09610.0920476386210.9840.11497.3
7.49-9.173.2370.07612.7517195505310.9850.09196.5
9.17-12.973.1970.06314.7713334384170.9910.07695.2
12.97-48.932.8890.05513.216762602340.9920.06890

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Phasing

PhasingMethod: molecular replacement
Phasing MRModel details: Phaser MODE: MR_AUTO
Highest resolutionLowest resolution
Rotation4.69 Å48.92 Å
Translation4.69 Å48.92 Å

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Processing

Software
NameVersionClassification
XSCALEdata scaling
PHASER2.8.3phasing
REFMAC5.8.0257refinement
PDB_EXTRACT3.25data extraction
XDSdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6DF0, 6UJ7

6df0

6uj7


Resolution: 2.9→48.93 Å / Cor.coef. Fo:Fc: 0.918 / Cor.coef. Fo:Fc free: 0.852 / SU B: 22.635 / SU ML: 0.418 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R Free: 0.507
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2868 973 5 %RANDOM
Rwork0.2137 ---
obs0.2173 18480 98.15 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 159.63 Å2 / Biso mean: 41.378 Å2 / Biso min: 18.82 Å2
Baniso -1Baniso -2Baniso -3
1-2 Å20 Å2-1.18 Å2
2--0.56 Å20 Å2
3----2.44 Å2
Refinement stepCycle: final / Resolution: 2.9→48.93 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6460 0 95 2 6557
Biso mean--85.66 28.9 -
Num. residues----818
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0136713
X-RAY DIFFRACTIONr_bond_other_d0.0010.0175905
X-RAY DIFFRACTIONr_angle_refined_deg1.5391.6539116
X-RAY DIFFRACTIONr_angle_other_deg1.3061.57913751
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.9515813
X-RAY DIFFRACTIONr_dihedral_angle_2_deg31.7421.983358
X-RAY DIFFRACTIONr_dihedral_angle_3_deg21.901151060
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.1071545
X-RAY DIFFRACTIONr_chiral_restr0.0670.2849
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.027499
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021448
LS refinement shellResolution: 2.901→2.976 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.393 70 -
Rwork0.307 1333 -
all-1403 -
obs--96.36 %

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