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- PDB-8udr: Structure of the P1B7 antibody bound to the Sotorasib-modified KR... -

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Entry
Database: PDB / ID: 8udr
TitleStructure of the P1B7 antibody bound to the Sotorasib-modified KRas G12C peptide presented by the A*03:01 MHC I complex
Components
  • Beta-2-microglobulin
  • GTPase KRas, N-terminally processed
  • HLA class I histocompatibility antigen, A alpha chain
  • P1B7 Heavy Chain
  • P1B7 Light Chain
KeywordsIMMUNE SYSTEM / antibody / MHC / haptenated peptide / PEPTIDE BINDING PROTEIN
Function / homology
Function and homology information


positive regulation of memory T cell activation / T cell mediated cytotoxicity directed against tumor cell target / 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 / response to mineralocorticoid / GMP binding / forebrain astrocyte development / antigen processing and presentation of endogenous peptide antigen via MHC class I via ER pathway, TAP-dependent / TAP complex binding ...positive regulation of memory T cell activation / T cell mediated cytotoxicity directed against tumor cell target / 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 / response to mineralocorticoid / GMP binding / forebrain astrocyte development / antigen processing and presentation of endogenous peptide antigen via MHC class I via ER pathway, TAP-dependent / TAP complex binding / antigen processing and presentation of exogenous peptide antigen via MHC class I / LRR domain binding / Golgi medial cisterna / regulation of synaptic transmission, GABAergic / negative regulation of epithelial cell differentiation / response to isolation stress / response to gravity / epithelial tube branching involved in lung morphogenesis / CD8 receptor binding / type I pneumocyte differentiation / protection from natural killer cell mediated cytotoxicity / Rac protein signal transduction / beta-2-microglobulin binding / myoblast proliferation / endoplasmic reticulum exit site / Signaling by RAS GAP mutants / Signaling by RAS GTPase mutants / Activation of RAS in B cells / TAP binding / RAS signaling downstream of NF1 loss-of-function variants / RUNX3 regulates p14-ARF / positive regulation of glial cell proliferation / skeletal muscle cell differentiation / SOS-mediated signalling / Activated NTRK3 signals through RAS / Activated NTRK2 signals through RAS / detection of bacterium / antigen processing and presentation of endogenous peptide antigen via MHC class Ib / antigen processing and presentation of endogenous peptide antigen via MHC class I via ER pathway, TAP-independent / cardiac muscle cell proliferation / 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 / positive regulation of Rac protein signal transduction / SHC-mediated cascade:FGFR3 / glial cell proliferation / MET activates RAS signaling / SHC-mediated cascade:FGFR2 / SHC-mediated cascade:FGFR4 / Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants / Signaling by PDGFRA extracellular domain mutants / PTK6 Regulates RHO GTPases, RAS GTPase and MAP kinases / Erythropoietin activates RAS / SHC-mediated cascade:FGFR1 / Signaling by FGFR4 in disease / T cell receptor binding / Signaling by CSF3 (G-CSF) / FRS-mediated FGFR3 signaling / Signaling by FLT3 ITD and TKD mutants / FRS-mediated FGFR2 signaling / FRS-mediated FGFR4 signaling / p38MAPK events / striated muscle cell differentiation / FRS-mediated FGFR1 signaling / Signaling by FGFR3 in disease / Tie2 Signaling / protein-membrane adaptor activity / Signaling by FGFR2 in disease / Signaling by FLT3 fusion proteins / GRB2 events in EGFR signaling / SHC1 events in EGFR signaling / FLT3 Signaling / Signaling by FGFR1 in disease / EGFR Transactivation by Gastrin / NCAM signaling for neurite out-growth / CD209 (DC-SIGN) signaling / Downstream signal transduction / GRB2 events in ERBB2 signaling / homeostasis of number of cells within a tissue / Insulin receptor signalling cascade / SHC1 events in ERBB2 signaling / early endosome lumen / Nef mediated downregulation of MHC class I complex cell surface expression / DAP12 interactions / Constitutive Signaling by Overexpressed ERBB2 / response to glucocorticoid / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / Ras activation upon Ca2+ influx through NMDA receptor / Endosomal/Vacuolar pathway / T cell mediated cytotoxicity / VEGFR2 mediated cell proliferation / small monomeric GTPase / Antigen Presentation: Folding, assembly and peptide loading of class I MHC / lumenal side of endoplasmic reticulum membrane / regulation of iron ion transport / FCERI mediated MAPK activation / cellular response to iron(III) ion / negative regulation of iron ion transport
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 / Class I Histocompatibility antigen, domains alpha 1 and 2 / Rho (Ras homology) subfamily of Ras-like small GTPases / 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 / Class I Histocompatibility antigen, domains alpha 1 and 2 / Rho (Ras homology) subfamily of Ras-like small GTPases / 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
AMG 510 (bound form) / GTPase KRas / HLA class I histocompatibility antigen, A alpha chain / Beta-2-microglobulin
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.1 Å
AuthorsChan, L.M. / Roweder, P.J. / Craik, C.S. / Verba, K.A.
Funding support United States, 3items
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, 2023Deposition site: RCSB / Processing site: RCSB
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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 alpha chain
B: Beta-2-microglobulin
C: GTPase KRas, N-terminally processed
D: P1B7 Heavy Chain
E: P1B7 Light Chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)91,6426
Polymers91,0795
Non-polymers5631
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

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Protein , 2 types, 2 molecules AB

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


Mass: 31757.953 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HLA-A / Production host: Escherichia coli (E. coli) / References: UniProt: P04439
#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

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Antibody , 2 types, 2 molecules DE

#4: Antibody P1B7 Heavy Chain


Mass: 24103.029 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Cell line (production host): HEK293T / Production host: Homo sapiens (human)
#5: Antibody P1B7 Light Chain


Mass: 22580.805 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Cell line (production host): HEK293T / Production host: Homo sapiens (human)

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

#3: Protein/peptide GTPase KRas, N-terminally processed


Mass: 889.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: P01116
#6: Chemical ChemComp-MOV / AMG 510 (bound form) / 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-4-[(2S)-2-methyl-4-propanoylpiperazin-1-yl]-1-[4-methyl-2-(propan-2-yl)pyridin-3-yl]pyrido[2,3-d]pyrimidin-2(1H)-one


Mass: 562.610 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C30H32F2N6O3 / Feature type: SUBJECT OF INVESTIGATION

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Details

Has ligand of interestY
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: P1B7 antibody:V7-Sotorasib A*03:01 MHC I complex / Type: COMPLEX / Entity ID: #1-#2, #4-#5, #3 / Source: RECOMBINANT
Molecular weightValue: 0.127044 MDa / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human) / Cell: HEK293T
Buffer solutionpH: 7.5 / Details: 20mM HEPES ph 7.5, 100 mM KCl
Buffer component
IDConc.NameFormulaBuffer-ID
120 mMHEPESC8H18N2O4S1
2100 mMPotassium ChlorideKCl1
SpecimenConc.: 0.0762 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277.15 K

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal magnification: 105000 X / Nominal defocus max: 20000 nm / Nominal defocus min: 7000 nm / Cs: 2.7 mm / C2 aperture diameter: 70 µm / Alignment procedure: COMA FREE
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingAverage exposure time: 2 sec. / Electron dose: 45.8 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) / Num. of grids imaged: 1 / Num. of real images: 3795
EM imaging opticsEnergyfilter name: GIF Bioquantum / Energyfilter slit width: 10 eV

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Processing

EM software
IDNameVersionCategoryDetails (eV)
1cryoSPARC4.3.1particle selection
2SerialEM4.1.0image acquisition
5cryoSPARC3.2.0CTF correctionPatch CTF
9PHENIXmodel refinement
14cryoSPARC3.2.03D reconstructionNU-Refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 1375850
3D reconstructionResolution: 3.1 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 286405 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0126561
ELECTRON MICROSCOPYf_angle_d1.5958938
ELECTRON MICROSCOPYf_dihedral_angle_d13.2232377
ELECTRON MICROSCOPYf_chiral_restr0.081962
ELECTRON MICROSCOPYf_plane_restr0.0161158

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