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

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Basic information

Entry
Database: PDB / ID: 6ulk
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
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 / antigen processing and presentation / Activated NTRK3 signals through RAS / Activated NTRK2 signals through RAS ...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 / antigen processing and presentation / Activated NTRK3 signals through RAS / Activated NTRK2 signals through RAS / 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 / FRS-mediated FGFR1 signaling / p38MAPK events / Tie2 Signaling / positive regulation of endothelial cell proliferation / Signaling by FGFR2 in disease / GRB2 events in EGFR signaling / SHC1 events in EGFR signaling / EGFR Transactivation by Gastrin / Signaling by FLT3 fusion proteins / FLT3 Signaling / Signaling by FGFR1 in disease / Ras activation upon Ca2+ influx through NMDA receptor / GRB2 events in ERBB2 signaling / NCAM signaling for neurite out-growth / CD209 (DC-SIGN) signaling / SHC1 events in ERBB2 signaling / Downstream signal transduction / Constitutive Signaling by Overexpressed ERBB2 / Insulin receptor signalling cascade / small monomeric GTPase / G protein activity / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / positive regulation of ferrous iron binding / positive regulation of transferrin receptor binding / VEGFR2 mediated cell proliferation / positive regulation of receptor binding / early endosome lumen / 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 / FCERI mediated MAPK activation / Antigen Presentation: Folding, assembly and peptide loading of class I MHC / Signaling by ERBB2 TMD/JMD mutants / RAF activation / Signaling by high-kinase activity BRAF mutants / cellular response to iron(III) ion / antigen processing and presentation of exogenous protein antigen via MHC class Ib, TAP-dependent / Constitutive Signaling by EGFRvIII / negative regulation of forebrain neuron differentiation / MAP2K and MAPK activation / Signaling by ERBB2 ECD mutants / ER to Golgi transport vesicle membrane / regulation of erythrocyte differentiation / peptide antigen assembly with MHC class I protein complex / response to molecule of bacterial origin / regulation of iron ion transport / MHC class I peptide loading complex / Signaling by ERBB2 KD Mutants / 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 / negative regulation of neurogenesis / peptide antigen assembly with MHC class II protein complex / positive regulation of receptor-mediated endocytosis / positive regulation of T cell mediated cytotoxicity / MHC class II protein complex / cellular response to nicotine / Regulation of RAS by GAPs / Negative regulation of MAPK pathway / recycling endosome membrane / RAS processing / specific granule lumen / 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 / 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: 1.9 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 / 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
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)44,5913
Polymers44,5913
Non-polymers00
Water2,666148
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4330 Å2
ΔGint-15 kcal/mol
Surface area18950 Å2
MethodPISA
Unit cell
Length a, b, c (Å)95.630, 77.053, 62.307
Angle α, β, γ (deg.)90.000, 120.597, 90.000
Int Tables number5
Space group name H-MC121
Space group name HallC2y
Symmetry operation#1: x,y,z
#2: -x,y,-z
#3: x+1/2,y+1/2,z
#4: -x+1/2,y+1/2,-z
Components on special symmetry positions
IDModelComponents
11B-144-

HOH

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Components

#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 / Beta-2 microglobulin


Mass: 11879.356 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
#3: Protein/peptide GLY-ALA-ASP-GLY-VAL-GLY-LYS-SER-ALA-LEU


Mass: 874.960 Da / Num. of mol.: 1 / Mutation: G12D / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: P01111
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 148 / Source method: isolated from a natural source / Formula: H2O

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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: 2.22 Å3/Da / Density % sol: 44.49 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop
Details: 0.1 M Bis-Tris pH 6.5, 0.05M CaCl2 dihydrate, 30% PEG MME 500

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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 EIGER X 16M / Detector: PIXEL / Date: Mar 3, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.88→33.44 Å / Num. obs: 30790 / % possible obs: 99.5 % / Redundancy: 5.3 % / Biso Wilson estimate: 21.93 Å2 / Rmerge(I) obs: 0.112 / Net I/σ(I): 21.8
Reflection shellResolution: 1.88→1.9 Å / Rmerge(I) obs: 0.395 / Num. unique obs: 1574

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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

4nt6


Resolution: 1.9→33.44 Å / SU ML: 0.2297 / Cross valid method: FREE R-VALUE / σ(F): 1.38 / Phase error: 29.3532
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2696 1508 4.93 %
Rwork0.2213 29059 -
obs0.2238 30567 99.41 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 31.56 Å2
Refinement stepCycle: LAST / Resolution: 1.9→33.44 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3139 0 0 148 3287
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00453223
X-RAY DIFFRACTIONf_angle_d0.70364370
X-RAY DIFFRACTIONf_chiral_restr0.047440
X-RAY DIFFRACTIONf_plane_restr0.0043580
X-RAY DIFFRACTIONf_dihedral_angle_d15.811911
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.9-1.960.31251150.2662647X-RAY DIFFRACTION99.53
1.96-2.030.30761450.25822671X-RAY DIFFRACTION99.96
2.03-2.110.29851230.24942645X-RAY DIFFRACTION99.89
2.11-2.210.28681450.24612630X-RAY DIFFRACTION100
2.21-2.330.27641310.2512656X-RAY DIFFRACTION100
2.33-2.470.3171390.25122638X-RAY DIFFRACTION99.96
2.47-2.660.29431380.25422652X-RAY DIFFRACTION100
2.66-2.930.31721500.2422642X-RAY DIFFRACTION99.93
2.93-3.350.29481370.22412642X-RAY DIFFRACTION99.93
3.35-4.220.21441340.18772676X-RAY DIFFRACTION99.79
4.22-33.440.23461510.18222560X-RAY DIFFRACTION94.69
Refinement TLS params.Method: refined / Origin x: 18.2435334974 Å / Origin y: 1.68102160926 Å / Origin z: 23.087645579 Å
111213212223313233
T0.0850587236525 Å2-0.0262905905797 Å2-0.000890434400188 Å2-0.184458689813 Å20.0268980094447 Å2--0.120865673165 Å2
L0.664511524439 °20.527496238376 °20.35899301812 °2-2.58028432114 °21.14455186347 °2--0.992685044425 °2
S-0.0941209279584 Å °0.0988096450924 Å °0.0144767175213 Å °-0.165803049824 Å °0.141519160711 Å °0.0138664603413 Å °-0.099066419443 Å °0.110327779692 Å °-0.0399931148001 Å °
Refinement TLS groupSelection details: all

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