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- PDB-8dvg: Structure of KRAS WT(7-16)-HLA-A*03:01 -

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Basic information

Entry
Database: PDB / ID: 8dvg
TitleStructure of KRAS WT(7-16)-HLA-A*03:01
Components
  • Beta-2-microglobulin
  • HLA class I histocompatibility antigen, A-3 alpha chain
  • VAL-VAL-VAL-GLY-ALA-GLY-GLY-VAL-GLY-LYS
KeywordsIMMUNE SYSTEM / immunotherapy / MHC-I / HLA-A3 / KRAS
Function / homology
Function and homology information


positive regulation of memory T cell activation / T cell mediated cytotoxicity directed against tumor cell target / TAP complex binding / Golgi medial cisterna / positive regulation of CD8-positive, alpha-beta T cell activation / CD8-positive, alpha-beta T cell activation / positive regulation of CD8-positive, alpha-beta T cell proliferation / CD8 receptor binding / antigen processing and presentation of exogenous peptide antigen via MHC class I / beta-2-microglobulin binding ...positive regulation of memory T cell activation / T cell mediated cytotoxicity directed against tumor cell target / TAP complex binding / Golgi medial cisterna / positive regulation of CD8-positive, alpha-beta T cell activation / CD8-positive, alpha-beta T cell activation / positive regulation of CD8-positive, alpha-beta T cell proliferation / CD8 receptor binding / antigen processing and presentation of exogenous peptide antigen via MHC class I / beta-2-microglobulin binding / endoplasmic reticulum exit site / antigen processing and presentation of endogenous peptide antigen via MHC class I via ER pathway, TAP-dependent / 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 / T cell receptor binding / : / : / 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 / regulation of iron ion transport / MHC class I peptide loading complex / response to molecule of bacterial origin / 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 / positive regulation of type II interferon production / specific granule lumen / recycling endosome membrane / phagocytic vesicle membrane / positive regulation of cellular senescence / 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 / antibacterial humoral response / late endosome membrane / sensory perception of smell / tertiary granule lumen / DAP12 signaling / E3 ubiquitin ligases ubiquitinate target proteins / T cell receptor signaling pathway / negative regulation of neuron projection development / iron ion transport / T cell differentiation in thymus / ER-Phagosome pathway / protein refolding / early endosome membrane / protein homotetramerization / amyloid fibril formation / intracellular iron ion homeostasis / learning or memory / defense response to Gram-positive bacterium / immune response / 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 / endoplasmic reticulum membrane / SARS-CoV-2 activates/modulates innate and adaptive immune responses / structural molecule activity / cell surface / endoplasmic reticulum / Golgi apparatus
Similarity search - Function
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 / 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 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 / 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 / 2-Layer Sandwich / Mainly Beta / Alpha Beta
Similarity search - Domain/homology
DI(HYDROXYETHYL)ETHER / HLA class I histocompatibility antigen, A alpha chain / Beta-2-microglobulin
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.594 Å
AuthorsWright, K.M. / Miller, M. / Gabelli, S.B.
Funding support United States, 4items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)P30 CA006973 United States
National Institutes of Health/National Cancer Institute (NIH/NCI)5T32 CA009071-38 United States
National Institutes of Health/National Cancer Institute (NIH/NCI)T32 GM73009 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)P41GM111244 United States
CitationJournal: Nat Commun / Year: 2023
Title: Hydrophobic interactions dominate the recognition of a KRAS G12V neoantigen.
Authors: Katharine M Wright / Sarah R DiNapoli / Michelle S Miller / P Aitana Azurmendi / Xiaowei Zhao / Zhiheng Yu / Mayukh Chakrabarti / WuXian Shi / Jacqueline Douglass / Michael S Hwang / Emily ...Authors: Katharine M Wright / Sarah R DiNapoli / Michelle S Miller / P Aitana Azurmendi / Xiaowei Zhao / Zhiheng Yu / Mayukh Chakrabarti / WuXian Shi / Jacqueline Douglass / Michael S Hwang / Emily Han-Chung Hsiue / Brian J Mog / Alexander H Pearlman / Suman Paul / Maximilian F Konig / Drew M Pardoll / Chetan Bettegowda / Nickolas Papadopoulos / Kenneth W Kinzler / Bert Vogelstein / Shibin Zhou / Sandra B Gabelli /
Abstract: Specificity remains a major challenge to current therapeutic strategies for cancer. Mutation associated neoantigens (MANAs) are products of genetic alterations, making them highly specific ...Specificity remains a major challenge to current therapeutic strategies for cancer. Mutation associated neoantigens (MANAs) are products of genetic alterations, making them highly specific therapeutic targets. MANAs are HLA-presented (pHLA) peptides derived from intracellular mutant proteins that are otherwise inaccessible to antibody-based therapeutics. Here, we describe the cryo-EM structure of an antibody-MANA pHLA complex. Specifically, we determine a TCR mimic (TCRm) antibody bound to its MANA target, the KRAS peptide presented by HLA-A*03:01. Hydrophobic residues appear to account for the specificity of the mutant G12V residue. We also determine the structure of the wild-type G12 peptide bound to HLA-A*03:01, using X-ray crystallography. Based on these structures, we perform screens to validate the key residues required for peptide specificity. These experiments led us to a model for discrimination between the mutant and the wild-type peptides presented on HLA-A*03:01 based exclusively on hydrophobic interactions.
History
DepositionJul 28, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 19, 2023Provider: repository / Type: Initial release
Revision 1.1Sep 6, 2023Group: Data collection / Database references
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / citation / citation_author
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
Revision 1.2Oct 25, 2023Group: Refinement description / Category: pdbx_initial_refinement_model
Revision 1.3Oct 23, 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, A-3 alpha chain
B: Beta-2-microglobulin
C: VAL-VAL-VAL-GLY-ALA-GLY-GLY-VAL-GLY-LYS
hetero molecules


Theoretical massNumber of molelcules
Total (without water)50,52017
Polymers49,1653
Non-polymers1,35514
Water2,000111
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6890 Å2
ΔGint-176 kcal/mol
Surface area18860 Å2
MethodPISA
Unit cell
Length a, b, c (Å)152.893, 152.893, 85.195
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number177
Space group name H-MP622
Components on special symmetry positions
IDModelComponents
11A-401-

HOH

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Components

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Protein , 2 types, 2 molecules AB

#1: Protein HLA class I histocompatibility antigen, A-3 alpha chain / MHC class I antigen A*3


Mass: 34589.211 Da / Num. of mol.: 1 / Fragment: UNP residues 25-304
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HLA-A, HLAA / Plasmid: pET3a / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: P04439
#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 / Plasmid: pET3a / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: P61769

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Protein/peptide , 1 types, 1 molecules C

#3: Protein/peptide VAL-VAL-VAL-GLY-ALA-GLY-GLY-VAL-GLY-LYS


Mass: 843.003 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human)

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Non-polymers , 3 types, 125 molecules

#4: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 13 / Source method: obtained synthetically / Formula: SO4
#5: Chemical ChemComp-PEG / DI(HYDROXYETHYL)ETHER


Mass: 106.120 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C4H10O3
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 111 / 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: 2.93 Å3/Da / Density % sol: 57.99 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop
Details: 0.2M ammonium sulfate 0.1M sodium cacodylate pH 6.5 30 % w/v PEG 8,000

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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: 0.97931 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Apr 2, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97931 Å / Relative weight: 1
ReflectionResolution: 2.59→19.65 Å / Num. obs: 18625 / % possible obs: 99.5 % / Redundancy: 10.3 % / CC1/2: 0.993 / Rmerge(I) obs: 0.24 / Rrim(I) all: 0.252 / Net I/σ(I): 8.97
Reflection shell
Resolution (Å)Rmerge(I) obsNum. unique obsCC1/2Rrim(I) allDiffraction-ID
2.6-2.661.18613300.7571.251
2.66-2.741.11413290.7711.1721
2.74-2.820.91712730.7980.9671
2.82-2.90.76212380.8630.8011
2.9-30.63212140.8940.6661
3-3.10.49611700.9390.521
3.1-3.220.41311340.9530.4331
3.22-3.350.31711030.9740.3321
3.35-3.50.27810520.980.2921
3.5-3.670.22710060.9860.2381
3.67-3.870.1839670.9910.1921
3.87-4.110.1579160.9930.1661
4.11-4.390.138660.9950.1371
4.39-4.740.1168140.9950.1221
4.74-5.190.1137470.9960.1191
5.19-5.810.1276820.9950.1331
5.81-6.710.1426200.9950.1491
6.71-8.210.0995290.9980.1051
8.21-11.620.0714290.9980.0751
11.62-19.650.0712060.9980.0751

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Phasing

PhasingMethod: molecular replacement
Phasing MRR rigid body: 0.392
Highest resolutionLowest resolution
Rotation19.65 Å3.5 Å

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Processing

Software
NameVersionClassification
PHENIX1.16refinement
XDSdata reduction
Aimless0.5.21data scaling
MOLREPphasing
PDB_EXTRACT3.25data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6O9B

6o9b


Resolution: 2.594→19.648 Å / SU ML: 0.27 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 21.51 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2276 906 4.86 %RANDOM
Rwork0.1913 ---
obs0.1931 18625 99.86 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.594→19.648 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3153 0 72 111 3336
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0023293
X-RAY DIFFRACTIONf_angle_d0.5174470
X-RAY DIFFRACTIONf_dihedral_angle_d15.6491915
X-RAY DIFFRACTIONf_chiral_restr0.041449
X-RAY DIFFRACTIONf_plane_restr0.003580
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.594-2.75560.2851520.25012857X-RAY DIFFRACTION99
2.7556-2.96770.29941500.24522901X-RAY DIFFRACTION100
2.9677-3.26520.2581440.21582910X-RAY DIFFRACTION100
3.2652-3.73480.25661350.18562958X-RAY DIFFRACTION100
3.7348-4.69490.16061600.14912959X-RAY DIFFRACTION100
4.6949-19.6480.22391650.18733134X-RAY DIFFRACTION100
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
11.1080.03890.67441.26380.3911.9341-0.02580.0022-0.00840.02670.0760.03780.09350.0724-0.03650.27880.00690.00490.21660.00620.259965.01596.339224.4195
23.6575-1.18620.9061.9906-0.08311.1028-0.03670.10920.6890.4666-0.0353-0.6523-0.4566-0.3047-0.0260.35870.06420.00340.38050.03840.219459.963716.736541.6383
34.4078-1.36030.832.5078-0.94452.20640.0732-0.2772-0.5718-0.0670.12160.49540.215-0.514-0.09050.41960.0444-0.00340.3644-0.00040.555136.833128.968324.3195
42.55951.0544-0.15126.36094.05287.0949-0.07460.1907-0.417-0.17850.10910.39540.460.2537-0.0140.40930.0612-0.0510.3383-0.01620.389553.614321.395511.727
51.30532.459-0.71635.3467-2.33981.76390.3265-0.34620.60761.0044-0.2628-0.1259-0.86560.0414-0.19010.65870.1255-0.0050.3942-0.060.475853.253342.325826.3923
61.00440.44210.83885.84831.26711.7954-0.1324-0.0233-0.0341-0.59890.0077-0.3153-0.40010.27280.09010.4215-0.0352-0.01020.30990.03990.356159.287928.279814.7144
71.8156-0.1467-0.5927.0952-2.3571.0017-0.39630.7437-0.14930.1388-0.198-1.118-0.63060.71770.34030.6538-0.1458-0.00950.40590.05350.620166.084136.502613.765
80.4092-0.6285-0.54556.22030.55061.30790.0884-0.12990.16670.2591-0.20640.4504-0.0720.15140.21870.30180.0091-0.05290.30990.02930.448159.209323.048419.8327
93.36840.83690.2241.8362-3.43537.508-0.50680.73070.8801-0.56820.04710.7466-0.8169-0.82410.43960.8192-0.0811-0.22850.64550.09360.94954.309847.552415.4526
101.3163-0.1859-0.1664.87910.87131.4065-0.01650.0757-0.0803-0.10380.0544-0.2077-0.44170.52810.01420.5821-0.02060.01690.31140.03060.369357.641428.2245.6651
114.82182.2291-0.92176.81753.62248.7417-0.3262-0.17150.7884-0.03980.53930.6337-0.087-1.4062-0.35030.58620.1507-0.08050.50910.17170.543749.723936.658313.4089
122.93210.21752.23285.71582.66186.0292-0.12750.6181-0.05520.22130.61780.07890.66090.2036-0.2970.1633-0.00380.00310.3250.00490.242869.64970.765126.6468
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 1 through 162 )
2X-RAY DIFFRACTION2chain 'A' and (resid 163 through 185 )
3X-RAY DIFFRACTION3chain 'A' and (resid 186 through 277 )
4X-RAY DIFFRACTION4chain 'B' and (resid 19 through 31 )
5X-RAY DIFFRACTION5chain 'B' and (resid 32 through 39 )
6X-RAY DIFFRACTION6chain 'B' and (resid 40 through 61 )
7X-RAY DIFFRACTION7chain 'B' and (resid 62 through 71 )
8X-RAY DIFFRACTION8chain 'B' and (resid 72 through 91 )
9X-RAY DIFFRACTION9chain 'B' and (resid 92 through 97 )
10X-RAY DIFFRACTION10chain 'B' and (resid 98 through 110 )
11X-RAY DIFFRACTION11chain 'B' and (resid 111 through 119 )
12X-RAY DIFFRACTION12chain 'C' and (resid 1 through 10 )

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