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- PDB-6uon: Molecular basis for tumor infiltrating TCR recognition of hotspot... -

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Basic information

Entry
Database: PDB / ID: 6uon
TitleMolecular basis for tumor infiltrating TCR recognition of hotspot KRAS-G12D mutation
Components
  • Beta-2-microglobulinBeta-2 microglobulin
  • GLY-ALA-ASP-GLY-VAL-GLY-LYS-SER-ALA-LEU
  • HLA class I antigen
  • TCR-V-alpha-12-02*01
  • TCR-V-beta-10-2*01
KeywordsIMMUNE SYSTEM / HLA-C Neoantigen KRAS
Function / homology
Function and homology information


myoblast differentiation / Signaling by RAS GAP mutants / Signaling by RAS GTPase mutants / Activation of RAS in B cells / tertiary granule membrane / RAS signaling downstream of NF1 loss-of-function variants / SOS-mediated signalling / Activated NTRK3 signals through RAS / Activated NTRK2 signals through RAS / antigen processing and presentation ...myoblast differentiation / Signaling by RAS GAP mutants / Signaling by RAS GTPase mutants / Activation of RAS in B cells / tertiary granule membrane / RAS signaling downstream of NF1 loss-of-function variants / SOS-mediated signalling / Activated NTRK3 signals through RAS / Activated NTRK2 signals through RAS / antigen processing and presentation / SHC1 events in ERBB4 signaling / Signalling to RAS / SHC-related events triggered by IGF1R / Activated NTRK2 signals through FRS2 and FRS3 / Estrogen-stimulated signaling through PRKCZ / SHC-mediated cascade:FGFR3 / MET activates RAS signaling / PTK6 Regulates RHO GTPases, RAS GTPase and MAP kinases / Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants / Signaling by PDGFRA extracellular domain mutants / SHC-mediated cascade:FGFR2 / SHC-mediated cascade:FGFR4 / Signaling by FGFR4 in disease / SHC-mediated cascade:FGFR1 / Erythropoietin activates RAS / FRS-mediated FGFR3 signaling / Signaling by FLT3 ITD and TKD mutants / FRS-mediated FGFR2 signaling / FRS-mediated FGFR4 signaling / Signaling by FGFR3 in disease / p38MAPK events / FRS-mediated FGFR1 signaling / Tie2 Signaling / Signaling by FGFR2 in disease / GRB2 events in EGFR signaling / SHC1 events in EGFR signaling / EGFR Transactivation by Gastrin / Signaling by FLT3 fusion proteins / Ras activation upon Ca2+ influx through NMDA receptor / FLT3 Signaling / Signaling by FGFR1 in disease / GRB2 events in ERBB2 signaling / positive regulation of endothelial cell proliferation / NCAM signaling for neurite out-growth / CD209 (DC-SIGN) signaling / SHC1 events in ERBB2 signaling / Downstream signal transduction / Insulin receptor signalling cascade / Constitutive Signaling by Overexpressed ERBB2 / small monomeric GTPase / G protein activity / positive regulation of ferrous iron binding / positive regulation of transferrin receptor binding / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / VEGFR2 mediated cell proliferation / early endosome lumen / positive regulation of receptor binding / Nef mediated downregulation of MHC class I complex cell surface expression / DAP12 interactions / negative regulation of receptor binding / lumenal side of endoplasmic reticulum membrane / Endosomal/Vacuolar pathway / Antigen Presentation: Folding, assembly and peptide loading of class I MHC / FCERI mediated MAPK activation / Signaling by ERBB2 TMD/JMD mutants / RAF activation / Signaling by high-kinase activity BRAF mutants / antigen processing and presentation of exogenous protein antigen via MHC class Ib, TAP-dependent / cellular response to iron(III) ion / Constitutive Signaling by EGFRvIII / MAP2K and MAPK activation / negative regulation of forebrain neuron differentiation / Signaling by ERBB2 ECD mutants / ER to Golgi transport vesicle membrane / peptide antigen assembly with MHC class I protein complex / response to molecule of bacterial origin / Signaling by ERBB2 KD Mutants / regulation of erythrocyte differentiation / regulation of iron ion transport / MHC class I peptide loading complex / Signaling by SCF-KIT / HFE-transferrin receptor complex / T cell mediated cytotoxicity / cellular response to iron ion / antigen processing and presentation of endogenous peptide antigen via MHC class I / positive regulation of T cell cytokine production / MHC class I protein complex / multicellular organismal-level iron ion homeostasis / positive regulation of T cell mediated cytotoxicity / peptide antigen assembly with MHC class II protein complex / negative regulation of neurogenesis / MHC class II protein complex / positive regulation of receptor-mediated endocytosis / cellular response to nicotine / Regulation of RAS by GAPs / Negative regulation of MAPK pathway / recycling endosome membrane / RAS processing / phagocytic vesicle membrane / specific granule lumen
Similarity search - Function
Small GTPase, Ras-type / small GTPase Ras family profile. / MHC class I, alpha chain, C-terminal / MHC_I C-terminus / MHC class I-like antigen recognition-like / Murine Class I Major Histocompatibility Complex, H2-DB; Chain A, domain 1 / Rho (Ras homology) subfamily of Ras-like small GTPases / Ras subfamily of RAS small GTPases / Small GTPase / Ras family ...Small GTPase, Ras-type / small GTPase Ras family profile. / MHC class I, alpha chain, C-terminal / MHC_I C-terminus / MHC class I-like antigen recognition-like / Murine Class I Major Histocompatibility Complex, H2-DB; Chain A, domain 1 / Rho (Ras homology) subfamily of Ras-like small GTPases / Ras subfamily of RAS small GTPases / Small GTPase / Ras family / MHC class I alpha chain, alpha1 alpha2 domains / Class I Histocompatibility antigen, domains alpha 1 and 2 / Rab subfamily of small GTPases / 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 / Small GTP-binding protein domain / 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 / Immunoglobulins / Immunoglobulin-like fold / Immunoglobulin-like / Sandwich / P-loop containing nucleoside triphosphate hydrolase / 2-Layer Sandwich / Mainly Beta / Alpha Beta
Similarity search - Domain/homology
HLA class I antigen / GTPase NRas / Beta-2-microglobulin
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.5 Å
AuthorsSun, P.D. / Sim, M.J.W.
CitationJournal: Proc.Natl.Acad.Sci.USA / Year: 2020
Title: High-affinity oligoclonal TCRs define effective adoptive T cell therapy targeting mutant KRAS-G12D.
Authors: Sim, M.J.W. / Lu, J. / Spencer, M. / Hopkins, F. / Tran, E. / Rosenberg, S.A. / Long, E.O. / Sun, P.D.
History
DepositionOct 15, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 27, 2020Provider: repository / Type: Initial release
Revision 1.1Jun 10, 2020Group: Database references / Category: citation / citation_author
Item: _citation.pdbx_database_id_PubMed / _citation.title ..._citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.2Jun 17, 2020Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.3Oct 11, 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
G: TCR-V-alpha-12-02*01
H: TCR-V-beta-10-2*01
I: TCR-V-alpha-12-02*01
J: TCR-V-beta-10-2*01
A: HLA class I antigen
B: Beta-2-microglobulin
C: GLY-ALA-ASP-GLY-VAL-GLY-LYS-SER-ALA-LEU
D: HLA class I antigen
E: Beta-2-microglobulin
F: GLY-ALA-ASP-GLY-VAL-GLY-LYS-SER-ALA-LEU


Theoretical massNumber of molelcules
Total (without water)188,49310
Polymers188,49310
Non-polymers00
Water0
1
G: TCR-V-alpha-12-02*01
H: TCR-V-beta-10-2*01
D: HLA class I antigen
E: Beta-2-microglobulin
F: GLY-ALA-ASP-GLY-VAL-GLY-LYS-SER-ALA-LEU


Theoretical massNumber of molelcules
Total (without water)94,2465
Polymers94,2465
Non-polymers00
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
I: TCR-V-alpha-12-02*01
J: TCR-V-beta-10-2*01
A: HLA class I antigen
B: Beta-2-microglobulin
C: GLY-ALA-ASP-GLY-VAL-GLY-LYS-SER-ALA-LEU


Theoretical massNumber of molelcules
Total (without water)94,2465
Polymers94,2465
Non-polymers00
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)65.399, 79.286, 197.710
Angle α, β, γ (deg.)90.000, 91.109, 90.000
Int Tables number4
Space group name H-MP1211
Space group name HallP2yb
Symmetry operation#1: x,y,z
#2: -x,y+1/2,-z

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Components

#1: Protein TCR-V-alpha-12-02*01


Mass: 22471.852 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Escherichia coli (E. coli)
#2: Protein TCR-V-beta-10-2*01


Mass: 27314.350 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Escherichia coli (E. coli)
#3: Protein HLA class I antigen / MHC class I antigen / MHC class I histocompatibility antigen


Mass: 31837.107 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HLA-Cw, HLA-C / Production host: Escherichia coli (E. coli) / References: UniProt: C1K0Y1
#4: Protein Beta-2-microglobulin / Beta-2 microglobulin


Mass: 11748.160 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: B2M, CDABP0092, HDCMA22P / Production host: Escherichia coli (E. coli) / References: UniProt: P61769
#5: Protein/peptide GLY-ALA-ASP-GLY-VAL-GLY-LYS-SER-ALA-LEU


Mass: 874.960 Da / Num. of mol.: 2 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: P01111

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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: 2.72 Å3/Da / Density % sol: 54.76 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop
Details: 12.5% PEG 4000, 0.1M Na Cacodylate pH 5.8, 0.2M (NH4)2SO4 and 10% glycerol

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 22-ID / Wavelength: 1 Å
DetectorType: DECTRIS EIGER2 X 16M / Detector: PIXEL / Date: Dec 15, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 3.5→50 Å / Num. obs: 26510 / % possible obs: 100 % / Redundancy: 8.9 % / Biso Wilson estimate: 113.26 Å2 / Rmerge(I) obs: 0.28 / Net I/σ(I): 16.7
Reflection shellResolution: 3.5→3.56 Å / Rmerge(I) obs: 1.11 / Mean I/σ(I) obs: 1.9 / Num. unique obs: 1293

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Processing

Software
NameVersionClassification
PHENIX1.16_3549refinement
HKL-2000data reduction
SCALEPACKdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4NT6, 4ZDH

4nt6

4zdh


Resolution: 3.5→49.42 Å / SU ML: 0.5276 / Cross valid method: FREE R-VALUE / σ(F): 1.91 / Phase error: 32.6864
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2943 1267 4.92 %
Rwork0.2516 24486 -
obs0.2534 25753 99.56 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 129.12 Å2
Refinement stepCycle: LAST / Resolution: 3.5→49.42 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms13108 0 0 0 13108
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.004713449
X-RAY DIFFRACTIONf_angle_d0.891518264
X-RAY DIFFRACTIONf_chiral_restr0.24531900
X-RAY DIFFRACTIONf_plane_restr0.00542414
X-RAY DIFFRACTIONf_dihedral_angle_d24.90434966
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
3.5-3.640.39691320.31432741X-RAY DIFFRACTION99.9
3.64-3.810.32481640.29472678X-RAY DIFFRACTION99.86
3.81-4.010.35321770.28222646X-RAY DIFFRACTION99.96
4.01-4.260.29911490.25282703X-RAY DIFFRACTION99.82
4.26-4.590.28661640.23742679X-RAY DIFFRACTION99.75
4.59-5.050.25851290.22132765X-RAY DIFFRACTION99.83
5.05-5.780.26991090.24142718X-RAY DIFFRACTION99.61
5.78-7.270.28641160.27442804X-RAY DIFFRACTION99.69
7.27-49.420.27681270.23612752X-RAY DIFFRACTION97.69

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