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

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Basic information

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 / antigen processing and presentation of peptide antigen via MHC class I / 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 / skeletal muscle cell differentiation / RAS signaling downstream of NF1 loss-of-function variants / RUNX3 regulates p14-ARF / positive regulation of glial cell proliferation / 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 / 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 / MET activates RAS signaling / SHC-mediated cascade:FGFR2 / PTK6 Regulates RHO GTPases, RAS GTPase and MAP kinases / Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants / Signaling by PDGFRA extracellular domain mutants / SHC-mediated cascade:FGFR4 / Erythropoietin activates RAS / Signaling by FGFR4 in disease / SHC-mediated cascade:FGFR1 / Signaling by CSF3 (G-CSF) / FRS-mediated FGFR3 signaling / Signaling by FLT3 ITD and TKD mutants / FRS-mediated FGFR2 signaling / FRS-mediated FGFR4 signaling / protein-membrane adaptor activity / p38MAPK events / FRS-mediated FGFR1 signaling / Signaling by FGFR3 in disease / Tie2 Signaling / striated muscle cell differentiation / Signaling by FGFR2 in disease / GRB2 events in EGFR signaling / SHC1 events in EGFR signaling / 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 / homeostasis of number of cells within a tissue / GRB2 events in ERBB2 signaling / Downstream signal transduction / Ras activation upon Ca2+ influx through NMDA receptor / Insulin receptor signalling cascade / SHC1 events in ERBB2 signaling / 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 / lumenal side of endoplasmic reticulum membrane / 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 / cellular response to iron(III) ion / MHC class II protein complex / negative regulation of forebrain neuron differentiation / antigen processing and presentation of exogenous protein antigen via MHC class Ib, TAP-dependent / liver development / RAF activation / ER to Golgi transport vesicle membrane / Signaling by ERBB2 TMD/JMD mutants / female pregnancy / peptide antigen assembly with MHC class I protein complex / regulation of erythrocyte differentiation / regulation of iron ion transport / HFE-transferrin receptor complex / response to molecule of bacterial origin / MHC class I peptide loading complex / Signaling by SCF-KIT / Signaling by high-kinase activity BRAF 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 / 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: To Be Published
Title: Engineered antibodies that stabilize drug-modified KRASG12C neoantigens enable selective and potent cross-HLA immunotherapy
Authors: Maso L / Mosure SA / Rodriguez-Aponte SA / Pizzo A / Mensah DN / Southard M / Sze S / Vash B / Hattori T / Rajak E / Koide A / Neel BG / Koide S / Liu W / Toenjes ST / DaSilva-Jardine P / ...Authors: Maso L / Mosure SA / Rodriguez-Aponte SA / Pizzo A / Mensah DN / Southard M / Sze S / Vash B / Hattori T / Rajak E / Koide A / Neel BG / Koide S / Liu W / Toenjes ST / DaSilva-Jardine P / Chopra R / Rader C / Stopfer LE
History
DepositionFeb 21, 2025-
Header (metadata) releaseOct 8, 2025-
Map releaseOct 8, 2025-
UpdateOct 8, 2025-
Current statusOct 8, 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

Slices (1/3)

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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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AxesZYX

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Histogram

Histogram (log scale)

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Half map: #2

Fileemd_49361_half_map_1.map
Projections & Slices
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Histogram (log scale)

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Half map: #1

Fileemd_49361_half_map_2.map
Projections & Slices
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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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