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- EMDB-25427: Structure of KRAS G12V/HLA-A*03:01 in complex with antibody fragm... -
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Open data
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Basic information
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Title | Structure of KRAS G12V/HLA-A*03:01 in complex with antibody fragment V2 | |||||||||
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![]() | Complex / MHC-I / KRAS / HLA-A3 / IMMUNE SYSTEM | |||||||||
Function / homology | ![]() T cell mediated cytotoxicity directed against tumor cell target / positive regulation of memory T cell activation / TAP complex binding / positive regulation of CD8-positive, alpha-beta T cell activation / CD8-positive, alpha-beta T cell activation / Golgi medial cisterna / 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 / endoplasmic reticulum exit site ...T cell mediated cytotoxicity directed against tumor cell target / positive regulation of memory T cell activation / TAP complex binding / positive regulation of CD8-positive, alpha-beta T cell activation / CD8-positive, alpha-beta T cell activation / Golgi medial cisterna / 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 / 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 / beta-2-microglobulin binding / T cell receptor binding / detection of bacterium / positive regulation of ferrous iron binding / positive regulation of transferrin 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 / 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 / cellular response to iron ion / Endosomal/Vacuolar pathway / lumenal side of endoplasmic reticulum membrane / Antigen Presentation: Folding, assembly and peptide loading of class I MHC / cellular response to iron(III) ion / antigen processing and presentation of exogenous protein antigen via MHC class Ib, TAP-dependent / negative regulation of forebrain neuron differentiation / regulation of erythrocyte differentiation / peptide antigen assembly with MHC class I protein complex / ER to Golgi transport vesicle membrane / regulation of iron ion transport / response to molecule of bacterial origin / MHC class I peptide loading complex / 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 / MHC class I protein complex / multicellular organismal-level iron ion homeostasis / negative regulation of neurogenesis / positive regulation of receptor-mediated endocytosis / peptide antigen assembly with MHC class II protein complex / MHC class II protein complex / cellular response to nicotine / positive regulation of T cell mediated cytotoxicity / specific granule lumen / recycling endosome membrane / phagocytic vesicle membrane / positive regulation of type II interferon production / peptide antigen binding / positive regulation of cellular senescence / negative regulation of epithelial cell proliferation / antigen processing and presentation of exogenous peptide antigen via MHC class II / Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell / Interferon gamma signaling / positive regulation of immune response / Modulation by Mtb of host immune system / positive regulation of T cell activation / Interferon alpha/beta signaling / sensory perception of smell / negative regulation of neuron projection development / positive regulation of protein binding / tertiary granule lumen / DAP12 signaling / E3 ubiquitin ligases ubiquitinate target proteins / MHC class II protein complex binding / early endosome membrane / late endosome membrane / T cell receptor signaling pathway / iron ion transport / antibacterial humoral response / ER-Phagosome pathway / T cell differentiation in thymus / protein refolding / protein homotetramerization / intracellular iron ion homeostasis / amyloid fibril formation / learning or memory / defense response to Gram-positive bacterium / immune response / Amyloid fiber formation / Golgi membrane / endoplasmic reticulum lumen / external side of plasma membrane / lysosomal membrane / innate immune response / focal adhesion / signaling receptor binding / endoplasmic reticulum membrane / Neutrophil degranulation / SARS-CoV-2 activates/modulates innate and adaptive immune responses / structural molecule activity / cell surface / Golgi apparatus / endoplasmic reticulum Similarity search - Function | |||||||||
Biological species | ![]() | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 3.14 Å | |||||||||
![]() | Wright KM / Gabelli SB | |||||||||
Funding support | ![]()
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![]() | ![]() 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 |
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Structure visualization
Supplemental images |
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Downloads & links
-EMDB archive
Map data | ![]() | 6.9 MB | ![]() | |
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Header (meta data) | ![]() ![]() | 15.3 KB 15.3 KB | Display Display | ![]() |
Images | ![]() | 41.2 KB | ||
Filedesc metadata | ![]() | 6.1 KB | ||
Archive directory | ![]() ![]() | HTTPS FTP |
-Validation report
Summary document | ![]() | 326.4 KB | Display | ![]() |
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Full document | ![]() | 326 KB | Display | |
Data in XML | ![]() | 6.4 KB | Display | |
Data in CIF | ![]() | 7.3 KB | Display | |
Arichive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 7stfMC ![]() 8dvgC M: atomic model generated by this map C: citing same article ( |
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Similar structure data | Similarity search - Function & homology ![]() |
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Links
EMDB pages | ![]() ![]() |
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Related items in Molecule of the Month |
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Map
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Voxel size | X=Y=Z: 0.844 Å | ||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
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Sample components
-Entire : Ternary complex of antibody-fragment V2 with KRAS G12V/HLA-A*03:01
Entire | Name: Ternary complex of antibody-fragment V2 with KRAS G12V/HLA-A*03:01 |
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Components |
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-Supramolecule #1: Ternary complex of antibody-fragment V2 with KRAS G12V/HLA-A*03:01
Supramolecule | Name: Ternary complex of antibody-fragment V2 with KRAS G12V/HLA-A*03:01 type: complex / ID: 1 / Parent: 0 / Macromolecule list: all |
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-Macromolecule #1: IgG, Fab Heavy Chain V2
Macromolecule | Name: IgG, Fab Heavy Chain V2 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 23.175861 KDa |
Recombinant expression | Organism: Mammalian expression vector BsrGI-MCS-pcDNA3.1 (others) |
Sequence | String: EVQLVESGGG LVQPGGSLRL SCAASGFNLS YSDIHWVRQA PGKGLEWVAV VMPDSGHTNY ADSVKGRFTI SADTSKNTAY LQMNSLRAE DTAVYYCSRA TNIPVYAFDY WGQGTLVTVS SASTKGPSVF PLAPSSKSTS GGTAALGCLV KDYFPEPVTV S WNSGALTS ...String: EVQLVESGGG LVQPGGSLRL SCAASGFNLS YSDIHWVRQA PGKGLEWVAV VMPDSGHTNY ADSVKGRFTI SADTSKNTAY LQMNSLRAE DTAVYYCSRA TNIPVYAFDY WGQGTLVTVS SASTKGPSVF PLAPSSKSTS GGTAALGCLV KDYFPEPVTV S WNSGALTS GVHTFPAVLQ SSGLYSLSSV VTVPSSSLGT QTYICNVNHK PSNTKVDKKV EP |
-Macromolecule #2: KRAS G12V (7-16)
Macromolecule | Name: KRAS G12V (7-16) / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: synthetic construct (others) |
Molecular weight | Theoretical: 885.082 Da |
Sequence | String: VVVGAVGVGK |
-Macromolecule #3: IgG, Fab Light Chain V2
Macromolecule | Name: IgG, Fab Light Chain V2 / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 23.859516 KDa |
Recombinant expression | Organism: Mammalian expression vector BsrGI-MCS-pcDNA3.1 (others) |
Sequence | String: DIQMTQSPSS LSASVGDRVT ITCRASQDVN TAVAWYQQKP GKAPKLLIYS ASFLYSGVPS RFSGSRSGTD FTLTISSLQP EDFATYYCQ QSYYYFRPIT FGQGTKVEIK RTVAAPSVFI FPPSDEQLKS GTASVVCLLN NFYPREAKVQ WKVDNALQSG N SQESVTEQ ...String: DIQMTQSPSS LSASVGDRVT ITCRASQDVN TAVAWYQQKP GKAPKLLIYS ASFLYSGVPS RFSGSRSGTD FTLTISSLQP EDFATYYCQ QSYYYFRPIT FGQGTKVEIK RTVAAPSVFI FPPSDEQLKS GTASVVCLLN NFYPREAKVQ WKVDNALQSG N SQESVTEQ DSKDSTYSLS STLTLSKADY EKHKVYACEV THQGLSSPVT KSFNRGEC |
-Macromolecule #4: HLA class I histocompatibility antigen, A alpha chain
Macromolecule | Name: HLA class I histocompatibility antigen, A alpha chain / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 32.27051 KDa |
Recombinant expression | Organism: ![]() ![]() |
Sequence | String: GSHSMRYFFT SVSRPGRGEP RFIAVGYVDD TQFVRFDSDA ASQRMEPRAP WIEQEGPEYW DQETRNVKAQ SQTDRVDLGT LRGYYNQSE AGSHTIQIMY GCDVGSDGRF LRGYRQDAYD GKDYIALNED LRSWTAADMA AQITKRKWEA AHEAEQLRAY L DGTCVEWL ...String: GSHSMRYFFT SVSRPGRGEP RFIAVGYVDD TQFVRFDSDA ASQRMEPRAP WIEQEGPEYW DQETRNVKAQ SQTDRVDLGT LRGYYNQSE AGSHTIQIMY GCDVGSDGRF LRGYRQDAYD GKDYIALNED LRSWTAADMA AQITKRKWEA AHEAEQLRAY L DGTCVEWL RRYLENGKET LQRTDPPKTH MTHHPISDHE ATLRCWALGF YPAEITLTWQ RDGEDQTQDT ELVETRPAGD GT FQKWAAV VVPSGEEQRY TCHVQHEGLP KPLTLRWELS SQP UniProtKB: HLA class I histocompatibility antigen, A alpha chain |
-Macromolecule #5: Beta-2-microglobulin
Macromolecule | Name: Beta-2-microglobulin / type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 11.948353 KDa |
Recombinant expression | Organism: ![]() ![]() |
Sequence | String: EAIQRTPKIQ VYSRHPAENG KSNFLNCYVS GFHPSDIEVD LLKNGERIEK VEHSDLSFSK DWSFYLLYYT EFTPTEKDEY ACRVNHVTL SQPKIVKWDR DM UniProtKB: Beta-2-microglobulin |
-Experimental details
-Structure determination
Method | cryo EM |
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![]() | single particle reconstruction |
Aggregation state | particle |
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Sample preparation
Concentration | 1 mg/mL |
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Buffer | pH: 7 |
Vitrification | Cryogen name: ETHANE |
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Electron microscopy
Microscope | FEI TITAN KRIOS |
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Image recording | Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 60.0 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: ![]() |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD |
Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |
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Image processing
Startup model | Type of model: NONE |
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Final reconstruction | Resolution.type: BY AUTHOR / Resolution: 3.14 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 3.1beta) / Number images used: 367584 |
Initial angle assignment | Type: MAXIMUM LIKELIHOOD / Software - Name: RELION (ver. 3.1beta) |
Final angle assignment | Type: MAXIMUM LIKELIHOOD / Software - Name: RELION (ver. 3.1beta) |
-Atomic model buiding 1
Refinement | Space: REAL / Protocol: RIGID BODY FIT / Target criteria: Correlation coefficient |
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Output model | ![]() PDB-7stf: |