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- EMDB-42151: Structure of the P1B7 antibody bound to the Sotorasib-modified KR... -

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Entry
Database: EMDB / ID: EMD-42151
TitleStructure of the P1B7 antibody bound to the Sotorasib-modified KRas G12C peptide presented by the A*03:01 MHC I complex
Map data
Sample
  • Complex: P1B7 antibody:V7-Sotorasib A*03:01 MHC I complex
    • Protein or peptide: HLA class I histocompatibility antigen, A alpha chain
    • Protein or peptide: Beta-2-microglobulin
    • Protein or peptide: P1B7 Heavy Chain
    • Protein or peptide: P1B7 Light Chain
    • Protein or peptide: GTPase KRas, N-terminally processed
  • Ligand: AMG 510 (bound form)
Keywordsantibody / MHC / haptenated peptide / PEPTIDE BINDING PROTEIN / IMMUNE SYSTEM
Function / homology
Function and homology information


forebrain astrocyte development / 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 / negative regulation of epithelial cell differentiation / type I pneumocyte differentiation ...forebrain astrocyte development / 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 / negative regulation of epithelial cell differentiation / type I pneumocyte differentiation / regulation of synaptic transmission, GABAergic / epithelial tube branching involved in lung morphogenesis / CD8 receptor binding / Rac protein signal transduction / antigen processing and presentation of exogenous peptide antigen via MHC class I / beta-2-microglobulin binding / positive regulation of Rac protein signal transduction / endoplasmic reticulum exit site / Signaling by RAS GAP mutants / Signaling by RAS GTPase mutants / Activation of RAS in B cells / antigen processing and presentation of endogenous peptide antigen via MHC class I via ER pathway, TAP-dependent / skeletal muscle cell differentiation / TAP binding / RAS signaling downstream of NF1 loss-of-function variants / protection from natural killer cell mediated cytotoxicity / RUNX3 regulates p14-ARF / SOS-mediated signalling / Activated NTRK3 signals through RAS / Activated NTRK2 signals through RAS / antigen processing and presentation of endogenous peptide antigen via MHC class I via ER pathway, TAP-independent / SHC1 events in ERBB4 signaling / antigen processing and presentation of endogenous peptide antigen via MHC class Ib / Signalling to RAS / Activated NTRK2 signals through FRS2 and FRS3 / SHC-related events triggered by IGF1R / Estrogen-stimulated signaling through PRKCZ / glial cell proliferation / SHC-mediated cascade:FGFR3 / detection of bacterium / 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 / T cell receptor binding / FRS-mediated FGFR3 signaling / Signaling by CSF3 (G-CSF) / Signaling by FLT3 ITD and TKD mutants / protein-membrane adaptor activity / FRS-mediated FGFR2 signaling / FRS-mediated FGFR4 signaling / Signaling by FGFR3 in disease / p38MAPK events / FRS-mediated FGFR1 signaling / Tie2 Signaling / positive regulation of glial cell proliferation / Signaling by FGFR2 in disease / striated muscle cell differentiation / GRB2 events in EGFR signaling / SHC1 events in EGFR signaling / homeostasis of number of cells within a tissue / 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 / Nef mediated downregulation of MHC class I complex cell surface expression / negative regulation of receptor binding / DAP12 interactions / VEGFR2 mediated cell proliferation / 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 / antigen processing and presentation of exogenous protein antigen via MHC class Ib, TAP-dependent / cellular response to iron(III) ion / MHC class II protein complex / negative regulation of forebrain neuron differentiation / RAF activation / Signaling by ERBB2 TMD/JMD mutants
Similarity search - Function
Small GTPase, Ras-type / Small GTPase Ras domain profile. / Ran (Ras-related nuclear proteins) /TC4 subfamily of small GTPases / MHC class I, alpha chain, C-terminal / MHC_I C-terminus / MHC class I alpha chain, alpha1 alpha2 domains / Rho (Ras homology) subfamily of Ras-like small GTPases / Class I Histocompatibility antigen, domains alpha 1 and 2 / Ras subfamily of RAS small GTPases / Small GTPase ...Small GTPase, Ras-type / Small GTPase Ras domain profile. / Ran (Ras-related nuclear proteins) /TC4 subfamily of small GTPases / MHC class I, alpha chain, C-terminal / MHC_I C-terminus / MHC class I alpha chain, alpha1 alpha2 domains / Rho (Ras homology) subfamily of Ras-like small GTPases / Class I Histocompatibility antigen, domains alpha 1 and 2 / Ras subfamily of RAS small GTPases / 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 / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
GTPase KRas / HLA class I histocompatibility antigen, A alpha chain / Beta-2-microglobulin
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.1 Å
AuthorsChan LM / Roweder PJ / Craik CS / Verba KA
Funding support United States, 3 items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)P41-GM103393 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)T32 GM 064337 United States
Howard Hughes Medical Institute (HHMI) United States
CitationJournal: Cancer Res / Year: 2025
Title: Therapeutic Targeting and Structural Characterization of a Sotorasib-Modified KRAS G12C-MHC I Complex Demonstrate the Antitumor Efficacy of Hapten-Based Strategies.
Authors: Apurva Pandey / Peter J Rohweder / Lieza M Chan / Chayanid Ongpipattanakul / Dong Hee Chung / Bryce Paolella / Fiona M Quimby / Ngoc Nguyen / Kliment A Verba / Michael J Evans / Charles S Craik /
Abstract: Antibody-based therapies have emerged as a powerful strategy for the management of diverse cancers. Unfortunately, tumor-specific antigens remain challenging to identify and target. Recent work ...Antibody-based therapies have emerged as a powerful strategy for the management of diverse cancers. Unfortunately, tumor-specific antigens remain challenging to identify and target. Recent work established that inhibitor-modified peptide adducts derived from KRAS G12C are competent for antigen presentation via MHC I and can be targeted by antibody-based therapeutics, offering a means to directly target an intracellular oncoprotein at the cell surface with combination therapies. Here, we validated the antigen display of "haptenated" KRAS G12C peptide fragments on tumors in mouse models treated with the FDA-approved KRAS G12C covalent inhibitor sotorasib using PET/CT imaging of an 89Zr-labeled P1B7 IgG antibody, which selectively binds sotorasib-modified KRAS G12C-MHC I complexes. Targeting this peptide-MHC I complex with radioligand therapy using 225Ac- or 177Lu-P1B7 IgG effectively inhibited tumor growth in combination with sotorasib. Elucidation of the 3.1 Å cryo-EM structure of P1B7 bound to a haptenated KRAS G12C peptide-MHC I complex confirmed that the sotorasib-modified KRAS G12C peptide is presented via a canonical binding pose and showed that P1B7 binds the complex in a T-cell receptor-like manner. Together, these findings demonstrate the potential value of targeting unique oncoprotein-derived, haptenated MHC I complexes with radioligand therapeutics and provide a structural framework for developing next generation antibodies. Significance: Radioligand therapy using an antibody targeting KRAS-derived, sotorasib-modified MHC I complexes elicits antitumor effects superior to those of sotorasib alone and provides a potential strategy to repurpose sotorasib as a hapten to overcome resistance.
History
DepositionSep 28, 2023-
Header (metadata) releaseOct 16, 2024-
Map releaseOct 16, 2024-
UpdateMay 14, 2025-
Current statusMay 14, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_42151.png

Downloads & links

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Map

FileDownload / File: emd_42151.map.gz / Format: CCP4 / Size: 166.4 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

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AxesZ (Sec.)Y (Row.)X (Col.)
0.84 Å/pix.
x 352 pix.
= 293.92 Å		0.84 Å/pix.
x 352 pix.
= 293.92 Å		0.84 Å/pix.
x 352 pix.
= 293.92 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.835 Å
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Histogram (log scale)
Contour LevelBy AUTHOR: 0.404
Minimum - Maximum-3.0880804 - 4.8604445
Average (Standard dev.)-0.000117179006 (±0.06260596)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions352352352
Spacing352352352
CellA=B=C: 293.91998 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_42151_msk_1.map
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Additional map: #1

Fileemd_42151_additional_1.map
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Half map: #2

Fileemd_42151_half_map_1.map
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Half map: #1

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Sample components

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Entire : P1B7 antibody:V7-Sotorasib A*03:01 MHC I complex

EntireName: P1B7 antibody:V7-Sotorasib A*03:01 MHC I complex
Components
  • Complex: P1B7 antibody:V7-Sotorasib A*03:01 MHC I complex
    • Protein or peptide: HLA class I histocompatibility antigen, A alpha chain
    • Protein or peptide: Beta-2-microglobulin
    • Protein or peptide: P1B7 Heavy Chain
    • Protein or peptide: P1B7 Light Chain
    • Protein or peptide: GTPase KRas, N-terminally processed
  • Ligand: AMG 510 (bound form)

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Supramolecule #1: P1B7 antibody:V7-Sotorasib A*03:01 MHC I complex

SupramoleculeName: P1B7 antibody:V7-Sotorasib A*03:01 MHC I complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2, #4-#5, #3
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 127.044 KDa

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Macromolecule #1: HLA class I histocompatibility antigen, A alpha chain

MacromoleculeName: HLA class I histocompatibility antigen, A alpha chain / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 31.757953 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: 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 KPLTLRWE

UniProtKB: HLA class I histocompatibility antigen, A alpha chain

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Macromolecule #2: Beta-2-microglobulin

MacromoleculeName: Beta-2-microglobulin / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 11.74816 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
IQRTPKIQVY SRHPAENGKS NFLNCYVSGF HPSDIEVDLL KNGERIEKVE HSDLSFSKDW SFYLLYYTEF TPTEKDEYAC RVNHVTLSQ PKIVKWDRDM

UniProtKB: Beta-2-microglobulin

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Macromolecule #3: GTPase KRas, N-terminally processed

MacromoleculeName: GTPase KRas, N-terminally processed / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 889.094 Da
SequenceString:
VVVGACGVGK

UniProtKB: GTPase KRas

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Macromolecule #4: P1B7 Heavy Chain

MacromoleculeName: P1B7 Heavy Chain / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 24.103029 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: VQLQQSGPGL VKPSQTLSLT CAISGDSVSS NSVAWNWIRQ SPSRGLEWLG RTYYRSKWYS DYAVSVKSRI TINPDTSKNQ FSLQLTSMT PEDTAVYYCA REGVTMGPGA FDIWGQGTMV TVSSASTKGP SVFPLAPSSK STSGGTAALG CLVKDYFPEP V TVSWNSGA ...String:
VQLQQSGPGL VKPSQTLSLT CAISGDSVSS NSVAWNWIRQ SPSRGLEWLG RTYYRSKWYS DYAVSVKSRI TINPDTSKNQ FSLQLTSMT PEDTAVYYCA REGVTMGPGA FDIWGQGTMV TVSSASTKGP SVFPLAPSSK STSGGTAALG CLVKDYFPEP V TVSWNSGA LTSGVHTFPA VLQSSGLYSL SSVVTVPSSS LGTQTYICNV NHKPSNTKVD KKVEPKSC

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Macromolecule #5: P1B7 Light Chain

MacromoleculeName: P1B7 Light Chain / type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 22.580805 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: ALTQPPSVSG SPGQSVTISC TGSSSDVGHY NRVSWYQQSP GTAPKLMIYD VSNRPSGAFS RFSGSRSGNT ASLTISGLQP EDEADYYCS SHRTGYTVEV FGTGTKVTVL GQPKAAPSVT LFPPSSEELQ ANKATLVCLI SDFYPGAVTV AWKADSSPVK A GVETTTPS ...String:
ALTQPPSVSG SPGQSVTISC TGSSSDVGHY NRVSWYQQSP GTAPKLMIYD VSNRPSGAFS RFSGSRSGNT ASLTISGLQP EDEADYYCS SHRTGYTVEV FGTGTKVTVL GQPKAAPSVT LFPPSSEELQ ANKATLVCLI SDFYPGAVTV AWKADSSPVK A GVETTTPS KQSNNKYAAS SYLSLTPEQW KSHRSYSCQV THEGSTVEKT VAPTE

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Macromolecule #6: AMG 510 (bound form)

MacromoleculeName: AMG 510 (bound form) / type: ligand / ID: 6 / Number of copies: 1 / Formula: MOV
Molecular weightTheoretical: 562.61 Da
Chemical component information

ChemComp-MOV:
AMG 510 (bound form)

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration0.0762 mg/mL
BufferpH: 7.5
Component:
ConcentrationFormulaName
20.0 mMC8H18N2O4SHEPES
100.0 mMKClPotassium Chloride

Details: 20mM HEPES ph 7.5, 100 mM KCl
GridModel: Quantifoil R1.2/1.3 / Material: GOLD / Mesh: 300 / Support film - #0 - Film type ID: 1 / Support film - #0 - Material: CARBON / Support film - #0 - topology: HOLEY / Support film - #1 - Film type ID: 2 / Support film - #1 - Material: GRAPHENE OXIDE
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277.15 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Specialist opticsEnergy filter - Name: GIF Bioquantum / Energy filter - Slit width: 10 eV
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Number grids imaged: 1 / Number real images: 3795 / Average exposure time: 2.0 sec. / Average electron dose: 45.8 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 70.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 20.0 µm / Nominal defocus min: 7.0 µm / Nominal magnification: 105000
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 1375850
CTF correctionSoftware - Name: cryoSPARC (ver. 3.2.0) / Software - details: Patch CTF / Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.1 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 3.2.0) / Software - details: NU-Refinement / Number images used: 286405
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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