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

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Basic information

Entry
Database: PDB / ID: 6ulr
TitleMolecular basis for tumor infiltrating TCR recognition of hotspot KRAS-G12D mutation
Components
  • Beta-2-microglobulin
  • GLY-ALA-ASP-GLY-VAL-GLY-LYS-SER-ALA
  • HLA class I antigen
  • TCR-V-alpha 4*01
  • TCR-V-beta 5-6*01
KeywordsIMMUNE SYSTEM / HLA-C Neoantigen KRAS
Function / homology
Function and homology information


myoblast differentiation / antigen processing and presentation of peptide antigen via MHC class I / 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 ...myoblast differentiation / antigen processing and presentation of peptide antigen via MHC class I / 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 / SHC1 events in ERBB4 signaling / Signalling to RAS / Activated NTRK2 signals through FRS2 and FRS3 / SHC-related events triggered by IGF1R / Estrogen-stimulated signaling through PRKCZ / SHC-mediated cascade:FGFR3 / MET activates RAS signaling / SHC-mediated cascade:FGFR2 / Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants / Signaling by PDGFRA extracellular domain mutants / PTK6 Regulates RHO GTPases, RAS GTPase and MAP kinases / SHC-mediated cascade:FGFR4 / Signaling by FGFR4 in disease / Erythropoietin activates RAS / SHC-mediated cascade:FGFR1 / 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 / Tie2 Signaling / FRS-mediated FGFR1 signaling / Signaling by FGFR2 in disease / positive regulation of endothelial cell proliferation / GRB2 events in EGFR signaling / SHC1 events in EGFR signaling / Signaling by FLT3 fusion proteins / FLT3 Signaling / Signaling by FGFR1 in disease / EGFR Transactivation by Gastrin / NCAM signaling for neurite out-growth / CD209 (DC-SIGN) signaling / GRB2 events in ERBB2 signaling / Downstream signal transduction / Ras activation upon Ca2+ influx through NMDA receptor / SHC1 events in ERBB2 signaling / Insulin receptor signalling cascade / Constitutive Signaling by Overexpressed ERBB2 / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / : / : / positive regulation of receptor binding / early endosome lumen / VEGFR2 mediated cell proliferation / Nef mediated downregulation of MHC class I complex cell surface expression / negative regulation of receptor binding / DAP12 interactions / small monomeric GTPase / 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 / FCERI mediated MAPK activation / peptide antigen assembly with MHC class II protein complex / cellular response to iron(III) ion / RAF activation / 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 / Signaling by ERBB2 TMD/JMD mutants / ER to Golgi transport vesicle membrane / peptide antigen assembly with MHC class I protein complex / regulation of erythrocyte differentiation / regulation of iron ion transport / Signaling by high-kinase activity BRAF mutants / MHC class I peptide loading complex / response to molecule of bacterial origin / Signaling by SCF-KIT / HFE-transferrin receptor complex / Constitutive Signaling by EGFRvIII / MAP2K and MAPK activation / T cell mediated cytotoxicity / Signaling by ERBB2 ECD mutants / antigen processing and presentation of endogenous peptide antigen via MHC class I / positive regulation of T cell cytokine production / Signaling by ERBB2 KD Mutants / 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
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 / MHC class I alpha chain, alpha1 alpha2 domains / Rho (Ras homology) subfamily of Ras-like small GTPases / Ras subfamily of RAS small GTPases / Class I Histocompatibility antigen, domains alpha 1 and 2 ...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 / MHC class I alpha chain, alpha1 alpha2 domains / Rho (Ras homology) subfamily of Ras-like small GTPases / Ras subfamily of RAS small GTPases / Class I Histocompatibility antigen, domains alpha 1 and 2 / Small GTPase / Ras family / Beta-2-Microglobulin / : / MHC class I-like antigen recognition-like / MHC class I-like antigen recognition-like superfamily / Rab subfamily of small GTPases / 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 / Immunoglobulin-like fold / Immunoglobulins / 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: 3.2 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 8, 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 / Derived calculations
Category: citation / citation_author ...citation / citation_author / pdbx_struct_assembly_gen / pdbx_struct_oper_list
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
Revision 1.4Oct 30, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: HLA class I antigen
B: Beta-2-microglobulin
C: GLY-ALA-ASP-GLY-VAL-GLY-LYS-SER-ALA
D: TCR-V-alpha 4*01
E: TCR-V-beta 5-6*01


Theoretical massNumber of molelcules
Total (without water)94,4925
Polymers94,4925
Non-polymers00
Water45025
1
A: HLA class I antigen
B: Beta-2-microglobulin
C: GLY-ALA-ASP-GLY-VAL-GLY-LYS-SER-ALA

D: TCR-V-alpha 4*01
E: TCR-V-beta 5-6*01


Theoretical massNumber of molelcules
Total (without water)94,4925
Polymers94,4925
Non-polymers00
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation1_455x-1,y,z1
Unit cell
Length a, b, c (Å)73.031, 73.998, 107.899
Angle α, β, γ (deg.)90.000, 101.458, 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

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Protein , 4 types, 4 molecules ABDE

#1: Protein HLA class I antigen / MHC class I antigen / MHC class I histocompatibility antigen


Mass: 31837.107 Da / Num. of mol.: 1
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
#2: Protein Beta-2-microglobulin


Mass: 11748.160 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 (E. coli) / References: UniProt: P61769
#4: Protein TCR-V-alpha 4*01


Mass: 22651.082 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Escherichia coli (E. coli)
#5: Protein TCR-V-beta 5-6*01


Mass: 27493.381 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Escherichia coli (E. coli)

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Protein/peptide / Non-polymers , 2 types, 26 molecules C

#3: Protein/peptide GLY-ALA-ASP-GLY-VAL-GLY-LYS-SER-ALA / GTPase NRas


Mass: 761.802 Da / Num. of mol.: 1 / Mutation: G12D / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: P01111
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 25 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 3.02 Å3/Da / Density % sol: 59.33 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / Details: 22% PEG 3350, 0.1M MOPS pH 7.1 and 0.25M MgSO4

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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: Jun 22, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 3.2→39.827 Å / Num. obs: 17905 / % possible obs: 95.9 % / Redundancy: 5.4 % / Biso Wilson estimate: 44.73 Å2 / Rmerge(I) obs: 0.174 / Net I/σ(I): 25
Reflection shellResolution: 3.2→3.4 Å / Rmerge(I) obs: 0.488 / Mean I/σ(I) obs: 9.3 / Num. unique obs: 874

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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, 6AVG

4nt6

6avg


Resolution: 3.2→39.82 Å / SU ML: 0.4246 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 25.751
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2621 821 4.61 %
Rwork0.2219 16979 -
obs0.2238 17800 94.72 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 45.04 Å2
Refinement stepCycle: LAST / Resolution: 3.2→39.82 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6487 0 0 25 6512
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00236652
X-RAY DIFFRACTIONf_angle_d0.51459038
X-RAY DIFFRACTIONf_chiral_restr0.0413947
X-RAY DIFFRACTIONf_plane_restr0.00351198
X-RAY DIFFRACTIONf_dihedral_angle_d27.93072454
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
3.2-3.40.33721230.26292505X-RAY DIFFRACTION85.32
3.4-3.670.28081340.22592826X-RAY DIFFRACTION94.66
3.67-4.030.24991310.22462859X-RAY DIFFRACTION96.58
4.03-4.620.23441330.19832923X-RAY DIFFRACTION97.54
4.62-5.810.26071620.20942890X-RAY DIFFRACTION97.29
5.81-39.820.25141380.2352976X-RAY DIFFRACTION96.74

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