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- EMDB-29221: CryoEM structure of HLA-A2 MAGEA4 (286-294) in complex with H2aM3... -

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Entry
Database: EMDB / ID: EMD-29221
TitleCryoEM structure of HLA-A2 MAGEA4 (286-294) in complex with H2aM31345N Fab and 2M2 Fab
Map data
Sample
  • Complex: HLA-A2 MAGEA4 (286-294) complex with H2aM31345N Fab and 2M2 Fab
    • Complex: MHC class I antigen, Beta-2-microglobulin
      • Protein or peptide: MHC class I antigen
      • Protein or peptide: Beta-2-microglobulin
    • Complex: Melanoma-associated antigen 4 peptide
      • Protein or peptide: Melanoma-associated antigen 4 peptide
    • Complex: H2aM31345N Fab heavy chain, H2aM31345N Fab light chain
      • Protein or peptide: H2aM31345N Fab heavy chain
      • Protein or peptide: H2aM31345N Fab light chain
KeywordsHLA / MHC / IMMUNE SYSTEM / antibody
Function / homology
Function and homology information


antigen processing and presentation of peptide antigen via MHC class I / negative regulation of receptor binding / early endosome lumen / Nef mediated downregulation of MHC class I complex cell surface expression / DAP12 interactions / transferrin transport / 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 ...antigen processing and presentation of peptide antigen via MHC class I / negative regulation of receptor binding / early endosome lumen / Nef mediated downregulation of MHC class I complex cell surface expression / DAP12 interactions / transferrin transport / 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 / 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 / ER to Golgi transport vesicle membrane / peptide antigen assembly with MHC class I protein complex / regulation of erythrocyte differentiation / regulation of iron ion transport / response to molecule of bacterial origin / MHC class I peptide loading complex / HFE-transferrin receptor complex / T cell mediated cytotoxicity / antigen processing and presentation of endogenous peptide antigen via MHC class I / positive regulation of T cell cytokine production / antigen processing and presentation of exogenous peptide antigen via MHC class II / positive regulation of immune response / MHC class I protein complex / positive regulation of T cell activation / peptide antigen binding / positive regulation of receptor-mediated endocytosis / negative regulation of neurogenesis / positive regulation of T cell mediated cytotoxicity / cellular response to nicotine / multicellular organismal-level iron ion homeostasis / histone deacetylase binding / Modulation by Mtb of host immune system / specific granule lumen / phagocytic vesicle membrane / recycling endosome membrane / Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell / Interferon gamma signaling / negative regulation of epithelial cell proliferation / MHC class II protein complex binding / late endosome membrane / sensory perception of smell / positive regulation of cellular senescence / tertiary granule lumen / DAP12 signaling / T cell differentiation in thymus / ER-Phagosome pathway / negative regulation of neuron projection development / protein refolding / early endosome membrane / protein homotetramerization / amyloid fibril formation / intracellular iron ion homeostasis / learning or memory / immune response / Amyloid fiber formation / endoplasmic reticulum lumen / Golgi membrane / lysosomal membrane / external side of plasma membrane / focal adhesion / Neutrophil degranulation / SARS-CoV-2 activates/modulates innate and adaptive immune responses / structural molecule activity / cell surface / endoplasmic reticulum / negative regulation of transcription by RNA polymerase II / Golgi apparatus / protein homodimerization activity / extracellular space / extracellular exosome / extracellular region / metal ion binding / identical protein binding / nucleus / membrane / plasma membrane / cytosol
Similarity search - Function
Melanoma associated antigen, N-terminal / Melanoma associated antigen family N terminal / Melanoma associated antigen family N terminal / MAGE conserved domain profile. / MAGE homology domain / Melanoma-associated antigen / MAGE homology domain, winged helix WH1 motif / MAGE homology domain, winged helix WH2 motif / MAGE homology domain / Melanoma-associated antigen ...Melanoma associated antigen, N-terminal / Melanoma associated antigen family N terminal / Melanoma associated antigen family N terminal / MAGE conserved domain profile. / MAGE homology domain / Melanoma-associated antigen / MAGE homology domain, winged helix WH1 motif / MAGE homology domain, winged helix WH2 motif / MAGE homology domain / Melanoma-associated antigen / 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 / Beta-2-Microglobulin / : / MHC class I-like antigen recognition-like / MHC class I-like antigen recognition-like superfamily / MHC classes I/II-like antigen recognition protein / : / 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
Similarity search - Domain/homology
Melanoma-associated antigen 8 / Beta-2-microglobulin / MHC class I antigen
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.06 Å
AuthorsSaotome K / Franklin MC
Funding support1 items
OrganizationGrant numberCountry
Other private
CitationJournal: Sci Transl Med / Year: 2025
Title: CAR T cells based on fully human T cell receptor-mimetic antibodies exhibit potent antitumor activity in vivo.
Authors: Robert Salzler / David J DiLillo / Kei Saotome / Kevin Bray / Katja Mohrs / Haun Hwang / Kamil J Cygan / Darshit Shah / Anna Rye-Weller / Kunal Kundu / Ashok Badithe / Xiaoqin Zhang / Elena ...Authors: Robert Salzler / David J DiLillo / Kei Saotome / Kevin Bray / Katja Mohrs / Haun Hwang / Kamil J Cygan / Darshit Shah / Anna Rye-Weller / Kunal Kundu / Ashok Badithe / Xiaoqin Zhang / Elena Garnova / Marcela Torres / Ankur Dhanik / Robert Babb / Frank J Delfino / Courtney Thwaites / Drew Dudgeon / Michael J Moore / Thomas Craig Meagher / Corinne E Decker / Tomasz Owczarek / John A Gleason / Xiaoran Yang / David Suh / Wen-Yi Lee / Richard Welsh / Douglas MacDonald / Johanna Hansen / Chunguang Guo / Jessica R Kirshner / Gavin Thurston / Tammy Huang / Matthew C Franklin / George D Yancopoulos / John C Lin / Lynn E Macdonald / Andrew J Murphy / Gang Chen / Olav Olsen / William C Olson /
Abstract: Monoclonal antibody therapies have transformed the lives of patients across a diverse range of diseases. However, antibodies can usually only access extracellular proteins, including the ...Monoclonal antibody therapies have transformed the lives of patients across a diverse range of diseases. However, antibodies can usually only access extracellular proteins, including the extracellular portions of membrane proteins that are expressed on the cell surface. In contrast, T cell receptors (TCRs) survey the entire cellular proteome when processed and presented as peptides in association with human leukocyte antigen (pHLA complexes). Antibodies that mimic TCRs by recognizing pHLA complexes have the potential to extend the reach of antibodies to this larger pool of targets and provide increased binding affinity and specificity. A major challenge in developing TCR mimetic (TCRm) antibodies is the limited sequence differences between the target pHLA complex relative to the large global repertoire of pHLA complexes. Here, we provide a comprehensive strategy for generating fully human TCRm antibodies across multiple HLA alleles, beginning with pHLA target discovery and validation and culminating in the engineering of TCRm-based chimeric antigen receptor T cells with potent antitumor activity. By incorporating mass spectrometry, bioinformatic predictions, HLA-humanized mice, antibody screening, and cryo-electron microscopy, we have established a pipeline to identify additional pHLA complex-specific antibodies with therapeutic potential.
History
DepositionDec 19, 2022-
Header (metadata) releaseDec 20, 2023-
Map releaseDec 20, 2023-
UpdateJul 2, 2025-
Current statusJul 2, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_29221.png

Downloads & links

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Map

FileDownload / File: emd_29221.map.gz / Format: CCP4 / Size: 178 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesX (Sec.)Y (Row.)Z (Col.)
0.85 Å/pix.
x 360 pix.
= 306. Å		0.85 Å/pix.
x 360 pix.
= 306. Å		0.85 Å/pix.
x 360 pix.
= 306. Å

Surface

Projections

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.85 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 10.0
Minimum - Maximum-35.487395999999997 - 60.124054000000001
Average (Standard dev.)-0.000000000004067 (±1.0)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderZYX
Origin000
Dimensions360360360
Spacing360360360
CellA=B=C: 306.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_29221_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_29221_half_map_2.map
Projections & Slices
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Histogram

Histogram (log scale)

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Sample components

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Entire : HLA-A2 MAGEA4 (286-294) complex with H2aM31345N Fab and 2M2 Fab

EntireName: HLA-A2 MAGEA4 (286-294) complex with H2aM31345N Fab and 2M2 Fab
Components
  • Complex: HLA-A2 MAGEA4 (286-294) complex with H2aM31345N Fab and 2M2 Fab
    • Complex: MHC class I antigen, Beta-2-microglobulin
      • Protein or peptide: MHC class I antigen
      • Protein or peptide: Beta-2-microglobulin
    • Complex: Melanoma-associated antigen 4 peptide
      • Protein or peptide: Melanoma-associated antigen 4 peptide
    • Complex: H2aM31345N Fab heavy chain, H2aM31345N Fab light chain
      • Protein or peptide: H2aM31345N Fab heavy chain
      • Protein or peptide: H2aM31345N Fab light chain

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Supramolecule #1: HLA-A2 MAGEA4 (286-294) complex with H2aM31345N Fab and 2M2 Fab

SupramoleculeName: HLA-A2 MAGEA4 (286-294) complex with H2aM31345N Fab and 2M2 Fab
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all

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Supramolecule #2: MHC class I antigen, Beta-2-microglobulin

SupramoleculeName: MHC class I antigen, Beta-2-microglobulin / type: complex / ID: 2 / Parent: 1 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)

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Supramolecule #3: Melanoma-associated antigen 4 peptide

SupramoleculeName: Melanoma-associated antigen 4 peptide / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #3

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Supramolecule #4: H2aM31345N Fab heavy chain, H2aM31345N Fab light chain

SupramoleculeName: H2aM31345N Fab heavy chain, H2aM31345N Fab light chain
type: complex / ID: 4 / Parent: 1 / Macromolecule list: #4-#5
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: 32.082512 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 PKPLTLRWEP

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: 11.879356 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
MIQRTPKIQV YSRHPAENGK SNFLNCYVSG FHPSDIEVDL LKNGERIEKV EHSDLSFSKD WSFYLLYYTE FTPTEKDEYA CRVNHVTLS QPKIVKWDRD M

UniProtKB: Beta-2-microglobulin

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Macromolecule #3: Melanoma-associated antigen 4 peptide

MacromoleculeName: Melanoma-associated antigen 4 peptide / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 1.08133 KDa
SequenceString:
KVLEHVVRV

UniProtKB: Melanoma-associated antigen 8

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Macromolecule #4: H2aM31345N Fab heavy chain

MacromoleculeName: H2aM31345N Fab heavy chain / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 23.831629 KDa
Recombinant expressionOrganism: Cricetulus griseus (Chinese hamster)
SequenceString: QVQLVESGGG LVKPGGSLRL SCAASGFTFS EYYMTWIRQA PGQGLEWVSY ISSSGFNIYY ADSVKGRFTI SRDNAKNSLF LQMNSLRVE DTAVYYCARE GVTDGMDVWG QGTTVTVSSA STKGPSVFPL APCSRSTSES TAALGCLVKD YFPEPVTVSW N SGALTSGV ...String:
QVQLVESGGG LVKPGGSLRL SCAASGFTFS EYYMTWIRQA PGQGLEWVSY ISSSGFNIYY ADSVKGRFTI SRDNAKNSLF LQMNSLRVE DTAVYYCARE GVTDGMDVWG QGTTVTVSSA STKGPSVFPL APCSRSTSES TAALGCLVKD YFPEPVTVSW N SGALTSGV HTFPAVLQSS GLYSLSSVVT VPSSSLGTKT YTCNVDHKPS NTKVDKRVES KYGPP

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Macromolecule #5: H2aM31345N Fab light chain

MacromoleculeName: H2aM31345N Fab light chain / type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 23.438967 KDa
Recombinant expressionOrganism: Cricetulus griseus (Chinese hamster)
SequenceString: DIQMTQSPSS LSASVGDRVT ITCRASQSIS SYLNWYQQKP GKAPKLLIYA ASSLQSGVPS RFSGSGSGTD FTLTISSLQP EDFATYYCQ QSYSTPPITF GQGTRLEIKR TVAAPSVFIF PPSDEQLKSG TASVVCLLNN FYPREAKVQW KVDNALQSGN S QESVTEQD ...String:
DIQMTQSPSS LSASVGDRVT ITCRASQSIS SYLNWYQQKP GKAPKLLIYA ASSLQSGVPS RFSGSGSGTD FTLTISSLQP EDFATYYCQ QSYSTPPITF GQGTRLEIKR TVAAPSVFIF PPSDEQLKSG TASVVCLLNN FYPREAKVQW KVDNALQSGN S QESVTEQD SKDSTYSLSS TLTLSKADYE KHKVYACEVT HQGLSSPVTK SFNRGEC

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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: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Specialist opticsEnergy filter - Name: GIF Bioquantum / Energy filter - Slit width: 20 eV
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 40.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.4 µm / Nominal defocus min: 1.4000000000000001 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: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.06 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 93015
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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