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- EMDB-70124: Structure of a synthetic antibody (RM010) in complex with a class... -

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Entry
Database: EMDB / ID: EMD-70124
TitleStructure of a synthetic antibody (RM010) in complex with a class I MHC presenting a hapten-peptide conjugate
Map data
Sample
  • Complex: Binary complex of Fab RM010 with adagrasib-conjugated KRAS G12C peptide presented by HLA-A11
    • Protein or peptide: MHC class I antigen
    • Protein or peptide: RM010 Fab light chain
    • Protein or peptide: RM010 Fab heavy chain
  • Protein or peptide: GTPase KRas, N-terminally processed
  • Ligand: [(2S)-4-[7-(8-chloronaphthalen-1-yl)-2-{[(2S)-1-methylpyrrolidin-2-yl]methoxy}-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile
KeywordsComplex / Fab / IMMUNE SYSTEM
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 / EGFR Transactivation by Gastrin / Signaling by FGFR1 in disease / NCAM signaling for neurite out-growth / GRB2 events in ERBB2 signaling / homeostasis of number of cells within a tissue / CD209 (DC-SIGN) signaling / Downstream signal transduction / Ras activation upon Ca2+ influx through NMDA receptor / SHC1 events in ERBB2 signaling / Insulin receptor signalling cascade / response to glucocorticoid / Constitutive Signaling by Overexpressed ERBB2 / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / VEGFR2 mediated cell proliferation / small monomeric GTPase / lumenal side of endoplasmic reticulum membrane / FCERI mediated MAPK activation / liver development / Signaling by ERBB2 TMD/JMD mutants / RAF activation / female pregnancy / ER to Golgi transport vesicle membrane / Signaling by high-kinase activity BRAF mutants / Signaling by SCF-KIT / Constitutive Signaling by EGFRvIII / regulation of long-term neuronal synaptic plasticity / MAP2K and MAPK activation / Signaling by ERBB2 ECD mutants / Signaling by ERBB2 KD Mutants / visual learning / MHC class I protein complex / Signaling by CSF1 (M-CSF) in myeloid cells / RAS processing / Regulation of RAS by GAPs / Negative regulation of MAPK pathway / cytoplasmic side of plasma membrane / phagocytic vesicle membrane / recycling endosome membrane / cytokine-mediated signaling pathway / Signaling by RAF1 mutants / Signaling by moderate kinase activity BRAF mutants / Paradoxical activation of RAF signaling by kinase inactive BRAF / Signaling downstream of RAS 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 / : / 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
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.88 Å
AuthorsHu Z / Rajak E / Maso L / Koide S
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI) United States
CitationJournal: Proc Natl Acad Sci U S A / Year: 2025
Title: Generation of actionable, cancer-specific neoantigens from KRAS(G12C) with adagrasib.
Authors: Lorenzo Maso / Epsa Rajak / Takamitsu Hattori / Zhengshan Hu / Akiko Koide / Benjamin G Neel / Shohei Koide /
Abstract: Effective immune therapy against cancer ideally should target a cancer-specific antigen, an antigen that is present exclusively in cancer cells. However, there is a paucity of cancer-specific ...Effective immune therapy against cancer ideally should target a cancer-specific antigen, an antigen that is present exclusively in cancer cells. However, there is a paucity of cancer-specific antigens that are endogenously produced. HapImmune™ technology utilizes covalent inhibitors directed to an intracellular cancer driver to create cancer-specific neoantigens in the form of drug-peptide conjugates presented by class I MHC molecules. Our previous study with sotorasib, an FDA-approved covalent inhibitor of KRAS(G12C), demonstrated that drug-treated cells produce such neoantigens and can be killed by T cell engagers directed against the drug-peptide/MHC complex. Thus, this technology can unite targeted and immune therapies. In the present study, we examined whether this approach could generalize to another FDA-approved KRAS(G12C) inhibitor, adagrasib, whose chemical structure and cysteine reactivity differ substantially from sotorasib. We developed antibodies selective to adagrasib-KRAS(G12C) peptides presented by HLA-A*03 and A*11 that also show cross-reactivity to other KRAS(G12C) inhibitors presented in the same manner. Cryoelectron microscopy structures revealed a mode of adagrasib-peptide/HLA recognition distinctly different from that of sotorasib-directed HapImmune antibodies. The antibodies in a bispecific T cell engager format killed adagrasib-resistant lung cancer cells upon adagrasib treatment. These results support the broad applicability of the HapImmune approach for creating actionable cancer-specific neoantigens and offer candidates for therapeutic development.
History
DepositionApr 9, 2025-
Header (metadata) releaseJul 23, 2025-
Map releaseJul 23, 2025-
UpdateAug 13, 2025-
Current statusAug 13, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_70124.png

Downloads & links

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Map

FileDownload / File: emd_70124.map.gz / Format: CCP4 / Size: 149.9 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 340 pix.
= 280.5 Å		0.83 Å/pix.
x 340 pix.
= 280.5 Å		0.83 Å/pix.
x 340 pix.
= 280.5 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.825 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.85
Minimum - Maximum-3.01757 - 4.4128876
Average (Standard dev.)0.0012807809 (±0.072720535)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions340340340
Spacing340340340
CellA=B=C: 280.5 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_70124_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_70124_half_map_2.map
Projections & Slices
AxesZYX

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Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Binary complex of Fab RM010 with adagrasib-conjugated KRAS G12C p...

EntireName: Binary complex of Fab RM010 with adagrasib-conjugated KRAS G12C peptide presented by HLA-A11
Components
  • Complex: Binary complex of Fab RM010 with adagrasib-conjugated KRAS G12C peptide presented by HLA-A11
    • Protein or peptide: MHC class I antigen
    • Protein or peptide: RM010 Fab light chain
    • Protein or peptide: RM010 Fab heavy chain
  • Protein or peptide: GTPase KRas, N-terminally processed
  • Ligand: [(2S)-4-[7-(8-chloronaphthalen-1-yl)-2-{[(2S)-1-methylpyrrolidin-2-yl]methoxy}-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile

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Supramolecule #1: Binary complex of Fab RM010 with adagrasib-conjugated KRAS G12C p...

SupramoleculeName: Binary complex of Fab RM010 with adagrasib-conjugated KRAS G12C peptide presented by HLA-A11
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1, #4, #3
Source (natural)Organism: Homo sapiens (human)

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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: 21.081148 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
GSHSMRYFYT SVSRPGRGEP RFIAVGYVDD TQFVRFDSDA ASQRMEPRAP WIEQEGPEYW DQETRNVKAQ SQTDRVDLGT LRGYYNQSE DGSHTIQIMY GCDVGPDGRF LRGYRQDAYD GKDYIALNED LRSWTAADMA AQITKRKWEA AHAAEQQRAY L EGRCVEWL RRYLENGKET LQR

UniProtKB: MHC class I antigen

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Macromolecule #2: GTPase KRas, N-terminally processed

MacromoleculeName: GTPase KRas, N-terminally processed / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 889.094 Da
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
VVVGACGVGK

UniProtKB: GTPase KRas

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Macromolecule #3: RM010 Fab heavy chain

MacromoleculeName: RM010 Fab heavy chain / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 12.432712 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
EVQLVESGGG LVQPGGSLRL SCAASGFTFS SSSIHWVRQA PGKGLEWVAS ISSSSGSTSY ADSVKGRFTI SADTSKNTAY LQMNSLRAE DTAVYYCARF QWYAMDYWGQ GTLVTVS

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Macromolecule #4: RM010 Fab light chain

MacromoleculeName: RM010 Fab light chain / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 11.914289 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
DIQMTQSPSS LSASVGDRVT ITCRASQSVS SAVAWYQQKP GKAPKLLIYS ASSLYSGVPS RFSGSRSGTD FTLTISSLQP EDFATYYCQ QSSWLYWLVT FGQGTKVEIK

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Macromolecule #5: [(2S)-4-[7-(8-chloronaphthalen-1-yl)-2-{[(2S)-1-methylpyrrolidin-...

MacromoleculeName: [(2S)-4-[7-(8-chloronaphthalen-1-yl)-2-{[(2S)-1-methylpyrrolidin-2-yl]methoxy}-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile
type: ligand / ID: 5 / Number of copies: 1 / Formula: A1B8E
Molecular weightTheoretical: 606.133 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

BufferpH: 7.4
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 47.31 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.5 µm / Nominal defocus min: 0.5 µm
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: PDB ENTRY
PDB model - PDB ID:

8vr9

Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.88 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 155365
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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Atomic model buiding 1

RefinementOverall B value: 106.4
Output model

PDB-9o55:
Structure of a synthetic antibody (RM010) in complex with a class I MHC presenting a hapten-peptide conjugate

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