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- EMDB-49361: Structure of the cross-HLA supertype antibody R302 bound to a cla... -

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Entry
Database: EMDB / ID: EMD-49361
TitleStructure of the cross-HLA supertype antibody R302 bound to a class I MHC presenting a divarasib-modified KRAS-G12C peptide on HLA-A*02
Map data
Sample
  • Complex: Binary complex of Fab R302 with divarasib-conjugated KRAS G12C peptide (5-14) presented by class I MHC having HLA-A*02:01
    • Protein or peptide: MHC class I antigen
    • Protein or peptide: Beta-2-microglobulin
    • Protein or peptide: GTPase KRas
    • Protein or peptide: R302 Fab light chain
    • Protein or peptide: R302 Fab heavy chain
  • Ligand: 1-{(3S)-4-[(7M)-7-[6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl]-6-chloro-8-fluoro-2-{[(2S)-1-methylpyrrolidin-2-yl]methoxy}quinazolin-4-yl]-3-methylpiperazin-1-yl}propan-1-one
KeywordsAntibody / Cancer-neoantigen / complex / PROTEIN BINDING
Function / homology
Function and homology information


response to mineralocorticoid / GMP binding / forebrain astrocyte development / LRR domain binding / 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 / type I pneumocyte differentiation ...response to mineralocorticoid / GMP binding / forebrain astrocyte development / LRR domain binding / 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 / type I pneumocyte differentiation / Rac protein signal transduction / positive regulation of Rac protein signal transduction / Signaling by RAS GAP mutants / Signaling by RAS GTPase mutants / Activation of RAS in B cells / myoblast proliferation / RAS signaling downstream of NF1 loss-of-function variants / RUNX3 regulates p14-ARF / skeletal muscle cell differentiation / positive regulation of glial cell proliferation / antigen processing and presentation of peptide antigen via MHC class I / SOS-mediated signalling / Activated NTRK3 signals through RAS / Activated NTRK2 signals through RAS / SHC1 events in ERBB4 signaling / cardiac muscle cell proliferation / 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 / glial cell proliferation / SHC-mediated cascade:FGFR2 / Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants / Signaling by PDGFRA extracellular domain mutants / SHC-mediated cascade:FGFR4 / PTK6 Regulates RHO GTPases, RAS GTPase and MAP kinases / Erythropoietin activates RAS / SHC-mediated cascade:FGFR1 / Signaling by FGFR4 in disease / 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 / Signaling by FGFR3 in disease / FRS-mediated FGFR1 signaling / protein-membrane adaptor activity / Tie2 Signaling / striated muscle cell differentiation / Signaling by FGFR2 in disease / GRB2 events in EGFR signaling / Signaling by FLT3 fusion proteins / 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 / GRB2 events in ERBB2 signaling / Downstream signal transduction / homeostasis of number of cells within a tissue / Insulin receptor signalling cascade / SHC1 events in ERBB2 signaling / Ras activation upon Ca2+ influx through NMDA receptor / response to glucocorticoid / Constitutive Signaling by Overexpressed ERBB2 / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / negative regulation of receptor binding / early endosome lumen / Nef mediated downregulation of MHC class I complex cell surface expression / DAP12 interactions / VEGFR2 mediated cell proliferation / transferrin transport / small monomeric GTPase / cellular response to iron ion / Endosomal/Vacuolar pathway / FCERI mediated MAPK activation / Antigen Presentation: Folding, assembly and peptide loading of class I MHC / peptide antigen assembly with MHC class II protein complex / lumenal side of endoplasmic reticulum membrane / cellular response to iron(III) ion / negative regulation of forebrain neuron differentiation / MHC class II protein complex / antigen processing and presentation of exogenous protein antigen via MHC class Ib, TAP-dependent / liver development / ER to Golgi transport vesicle membrane / Signaling by ERBB2 TMD/JMD mutants / peptide antigen assembly with MHC class I protein complex / female pregnancy / regulation of iron ion transport / RAF activation / regulation of erythrocyte differentiation / HFE-transferrin receptor complex / response to molecule of bacterial origin / MHC class I peptide loading complex / Signaling by SCF-KIT / Constitutive Signaling by EGFRvIII
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
MHC class I antigen / GTPase KRas / Beta-2-microglobulin
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.23 Å
AuthorsMaso L
Funding support1 items
OrganizationGrant numberCountry
Not funded
CitationJournal: Nat Commun / Year: 2025
Title: Engineered antibodies that stabilize drug-modified KRAS neoantigens enable selective and potent cross-HLA immunotherapy.
Authors: Lorenzo Maso / Sarah A Mosure / Sergio A Rodriguez-Aponte / Angelina Pizzo / Diamond N Mensah / Matthew Southard / Samantha Sze / Tanvir Ahmed / Brian Vash / Takamitsu Hattori / Epsa Rajak / ...Authors: Lorenzo Maso / Sarah A Mosure / Sergio A Rodriguez-Aponte / Angelina Pizzo / Diamond N Mensah / Matthew Southard / Samantha Sze / Tanvir Ahmed / Brian Vash / Takamitsu Hattori / Epsa Rajak / Akiko Koide / Benjamin G Neel / Shohei Koide / Weifeng Liu / Sean T Toenjes / Paul Da Silva Jardine / Rajesh Chopra / Christoph Rader / Lauren E Stopfer /
Abstract: Covalent inhibitors of oncoprotein KRAS have initial efficacy, but responses lack durability. Covalently modified oncoproteins are presented as MHC-restricted hapten-peptides (p*MHC) on the cancer ...Covalent inhibitors of oncoprotein KRAS have initial efficacy, but responses lack durability. Covalently modified oncoproteins are presented as MHC-restricted hapten-peptides (p*MHC) on the cancer cell surface, enabling combination of targeted therapy with immunotherapy to overcome drug resistance. Building on indirect evidence of KRAS-derived p*MHCs, we use immunopeptidomics to identify and directly quantify these synthetic neoantigens. To address challenges by their low copy number, we develop AETX-R114, a T cell engaging bispecific antibody with picomolar affinity for MHC-restricted sotorasib-modified KRAS peptides presented by three HLA-A3 supertype alleles. AETX-R114 dramatically increases the half-life and thereby the number of presented p*MHCs, enabling selective and potent killing of resistant cancer cells both in vitro and in vivo. To broaden the therapeutic potential of creating and targeting synthetic neoantigens, we further develop AETX-R302, which recognizes divarasib-modified KRAS peptides presented on alleles from the HLA-A2 and A3 supertypes. Cryo-EM structure determination reveals the molecular basis for breaking HLA supertype restriction. Collectively, our study illustrates how engineered antibodies can transform synthetic neoantigens into actionable cancer immunotherapy targets.
History
DepositionFeb 21, 2025-
Header (metadata) releaseOct 8, 2025-
Map releaseOct 8, 2025-
UpdateDec 31, 2025-
Current statusDec 31, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_49361.png

Downloads & links

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Map

FileDownload / File: emd_49361.map.gz / Format: CCP4 / Size: 216 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.83 Å/pix.
x 384 pix.
= 316.8 Å		0.83 Å/pix.
x 384 pix.
= 316.8 Å		0.83 Å/pix.
x 384 pix.
= 316.8 Å

Surface

Projections

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.825 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.5
Minimum - Maximum-1.9347107 - 2.885053
Average (Standard dev.)0.0022674683 (±0.048476007)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions384384384
Spacing384384384
CellA=B=C: 316.8 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_49361_msk_1.map
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Half map: #2

Fileemd_49361_half_map_1.map
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Half map: #1

Fileemd_49361_half_map_2.map
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Sample components

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Entire : Binary complex of Fab R302 with divarasib-conjugated KRAS G12C pe...

EntireName: Binary complex of Fab R302 with divarasib-conjugated KRAS G12C peptide (5-14) presented by class I MHC having HLA-A*02:01
Components
  • Complex: Binary complex of Fab R302 with divarasib-conjugated KRAS G12C peptide (5-14) presented by class I MHC having HLA-A*02:01
    • Protein or peptide: MHC class I antigen
    • Protein or peptide: Beta-2-microglobulin
    • Protein or peptide: GTPase KRas
    • Protein or peptide: R302 Fab light chain
    • Protein or peptide: R302 Fab heavy chain
  • Ligand: 1-{(3S)-4-[(7M)-7-[6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl]-6-chloro-8-fluoro-2-{[(2S)-1-methylpyrrolidin-2-yl]methoxy}quinazolin-4-yl]-3-methylpiperazin-1-yl}propan-1-one

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Supramolecule #1: Binary complex of Fab R302 with divarasib-conjugated KRAS G12C pe...

SupramoleculeName: Binary complex of Fab R302 with divarasib-conjugated KRAS G12C peptide (5-14) presented by class I MHC having HLA-A*02:01
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#5
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 100 KDa

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Macromolecule #1: MHC class I antigen

MacromoleculeName: MHC class I antigen / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 35.419988 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: MGSHSMRYFF TSVSRPGRGE PRFIAVGYVD DTQFVRFDSD AASQRMEPRA PWIEQEGPEY WDGETRKVKA HSQTHRVDLG TLRGYYNQS EAGSHTVQRM YGCDVGSDWR FLRGYHQYAY DGKDYIALKE DLRSWTAADM AAQTTKHKWE AAHVAEQLRA Y LEGTCVEW ...String:
MGSHSMRYFF TSVSRPGRGE PRFIAVGYVD DTQFVRFDSD AASQRMEPRA PWIEQEGPEY WDGETRKVKA HSQTHRVDLG TLRGYYNQS EAGSHTVQRM YGCDVGSDWR FLRGYHQYAY DGKDYIALKE DLRSWTAADM AAQTTKHKWE AAHVAEQLRA Y LEGTCVEW LRRYLENGKE TLQRTDAPKT HMTHHAVSDH EATLRCWALS FYPAEITLTW QRDGEDQTQD TELVETRPAG DG TFQKWAA VVVPSGQEQR YTCHVQHEGL PKPLTLRWEG GGSGLNDIFE AQKIEWHEGG GSHHHHHHHH

UniProtKB: MHC class I antigen

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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: 11.892291 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
GSIQRTPKIQ VYSRHPAENG KSNFLNCYVS GFHPSDIEVD LLKNGERIEK VEHSDLSFSK DWSFYLLYYT EFTPTEKDEY ACRVNHVTL SQPKIVKWDR DM

UniProtKB: Beta-2-microglobulin

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Macromolecule #3: GTPase KRas

MacromoleculeName: GTPase KRas / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO / EC number: small monomeric GTPase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 945.2 Da
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
KLVVVGACGV

UniProtKB: GTPase KRas

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Macromolecule #4: R302 Fab light chain

MacromoleculeName: R302 Fab light chain / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 23.972529 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: DIVMTQSPAT LSLSPGERAT LSCRASQSLS SSFLAWYQQK PGQAPRLLIY GASSRATGIP DRFSGSGSGT DFTLTISRLE PEDFAVYYC QQSESALTFG GGTKVEIKRT VAAPSVFIFP PSDSQLKSGT ASVVCLLNNF YPREAKVQWK VDNALQSGNS Q ESVTEQDS ...String:
DIVMTQSPAT LSLSPGERAT LSCRASQSLS SSFLAWYQQK PGQAPRLLIY GASSRATGIP DRFSGSGSGT DFTLTISRLE PEDFAVYYC QQSESALTFG GGTKVEIKRT VAAPSVFIFP PSDSQLKSGT ASVVCLLNNF YPREAKVQWK VDNALQSGNS Q ESVTEQDS KDSTYSLSST LTLSKADYEK HKVYACEVTH QGLSSPVTKS FNRGECGGGG SLPETG

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Macromolecule #5: R302 Fab heavy chain

MacromoleculeName: R302 Fab heavy chain / type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 24.136109 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: EVQLLESGGG VVQPGRSLRL SCAASGFTFS SYGMHWVRQA PGKGLEWVAV ISYDGSNKYY ADSVKGRFTI SRDNSKNTLY LQMNSLRAE DTAVYYCLYG GNSYGMDVWG QGTMVTVFNQ IKGPSVFPLA PSSKSTSGGT AALGCLVKDY FPEPVTVSWN S GALTSGVH ...String:
EVQLLESGGG VVQPGRSLRL SCAASGFTFS SYGMHWVRQA PGKGLEWVAV ISYDGSNKYY ADSVKGRFTI SRDNSKNTLY LQMNSLRAE DTAVYYCLYG GNSYGMDVWG QGTMVTVFNQ IKGPSVFPLA PSSKSTSGGT AALGCLVKDY FPEPVTVSWN S GALTSGVH TFPAVLQSSG LYSLSSVVTV PSSSLGTQTY ICNVNHKPSN TKVDKKVEPK SCDKTHT

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Macromolecule #6: 1-{(3S)-4-[(7M)-7-[6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-...

MacromoleculeName: 1-{(3S)-4-[(7M)-7-[6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl]-6-chloro-8-fluoro-2-{[(2S)-1-methylpyrrolidin-2-yl]methoxy}quinazolin-4-yl]-3-methylpiperazin-1-yl}propan-1-one
type: ligand / ID: 6 / Number of copies: 1 / Formula: A1AWR
Molecular weightTheoretical: 624.073 Da

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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

Concentration2.6 mg/mL
BufferpH: 7.4
GridModel: Quantifoil R0.6/1 / Material: COPPER / Mesh: 300 / Support film - Material: GOLD / Support film - topology: HOLEY / Pretreatment - Type: GLOW DISCHARGE
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV / Details: blot time 4 s blot force 5.

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 46.99 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 2.7 µm / Nominal defocus min: 0.6 µm / Nominal magnification: 105000
Sample stageCooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.23 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 65281
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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