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- PDB-8fja: CryoEM structure of HLA-A2 MAGEA4 (230-239) in complex with REGN6... -

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Basic information

Entry
Database: PDB / ID: 8fja
TitleCryoEM structure of HLA-A2 MAGEA4 (230-239) in complex with REGN6972 Fab
Components
  • Beta-2-microglobulin
  • MHC class I antigen
  • Melanoma-associated antigen 4 peptide
  • REGN6972 Fab heavy chain
  • REGN6972 Fab light chain
KeywordsIMMUNE SYSTEM / HLA / MHC / antibody
Function / homology
Function and homology information


antigen processing and presentation of peptide antigen via MHC class I / positive regulation of cell cycle / regulation of natural killer cell mediated immunity / early endosome lumen / Nef mediated downregulation of MHC class I complex cell surface expression / DAP12 interactions / Endosomal/Vacuolar pathway / Antigen Presentation: Folding, assembly and peptide loading of class I MHC / lumenal side of endoplasmic reticulum membrane / regulation of iron ion transport ...antigen processing and presentation of peptide antigen via MHC class I / positive regulation of cell cycle / regulation of natural killer cell mediated immunity / early endosome lumen / Nef mediated downregulation of MHC class I complex cell surface expression / DAP12 interactions / Endosomal/Vacuolar pathway / Antigen Presentation: Folding, assembly and peptide loading of class I MHC / lumenal side of endoplasmic reticulum membrane / regulation of iron ion transport / negative regulation of iron ion transport / negative regulation of forebrain neuron differentiation / antigen processing and presentation of exogenous peptide antigen via MHC class Ib / peptide antigen assembly with MHC class I protein complex / ER to Golgi transport vesicle membrane / HFE-transferrin receptor complex / MHC class I peptide loading complex / transferrin transport / negative regulation of receptor-mediated endocytosis / cellular response to iron ion / positive regulation of T cell cytokine production / antigen processing and presentation of endogenous peptide antigen via MHC class I / MHC class I protein complex / peptide antigen assembly with MHC class II protein complex / negative regulation of epithelial cell proliferation / cellular response to nicotine / negative regulation of neurogenesis / MHC class II protein complex / positive regulation of receptor-mediated endocytosis / positive regulation of immune response / specific granule lumen / antigen processing and presentation of exogenous peptide antigen via MHC class II / peptide antigen binding / recycling endosome membrane / phagocytic vesicle membrane / positive regulation of T cell activation / histone deacetylase binding / Interferon gamma signaling / Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell / sensory perception of smell / Modulation by Mtb of host immune system / tertiary granule lumen / positive regulation of cellular senescence / MHC class II protein complex binding / DAP12 signaling / late endosome membrane / ER-Phagosome pathway / early endosome membrane / amyloid fibril formation / protein homotetramerization / intracellular iron ion homeostasis / learning or memory / immune response / endoplasmic reticulum lumen / Amyloid fiber formation / external side of plasma membrane / Golgi membrane / lysosomal membrane / focal adhesion / negative regulation of apoptotic process / Neutrophil degranulation / SARS-CoV-2 activates/modulates innate and adaptive immune responses / negative regulation of transcription by RNA polymerase II / structural molecule activity / Golgi apparatus / cell surface / endoplasmic reticulum / protein homodimerization activity / : / extracellular exosome / extracellular region / membrane / metal ion binding / identical protein binding / nucleus / plasma membrane
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 4 / Beta-2-microglobulin / MHC class I antigen
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3 Å
AuthorsSaotome, K. / Franklin, M.C.
Funding support1items
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, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 20, 2023Provider: repository / Type: Initial release
Revision 1.1Oct 30, 2024Group: Data collection / Structure summary
Category: em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _em_admin.last_update
Revision 1.2May 21, 2025Group: Data collection / Database references / Category: citation / citation_author / em_admin
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
D: REGN6972 Fab light chain
E: REGN6972 Fab heavy chain
A: MHC class I antigen
B: Beta-2-microglobulin
C: Melanoma-associated antigen 4 peptide


Theoretical massNumber of molelcules
Total (without water)93,7895
Polymers93,7895
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Antibody REGN6972 Fab light chain


Mass: 23420.947 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Cricetulus griseus (Chinese hamster)
#2: Antibody REGN6972 Fab heavy chain


Mass: 25272.316 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Cricetulus griseus (Chinese hamster)
#3: Protein MHC class I antigen


Mass: 32082.512 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HLA-A*02:01 / Production host: Escherichia coli (E. coli) / References: UniProt: Q861F7
#4: Protein Beta-2-microglobulin


Mass: 11879.356 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
#5: Protein/peptide Melanoma-associated antigen 4 peptide / Cancer/testis antigen 1.4 / CT1.4 / MAGE-4 antigen / MAGE-41 antigen / MAGE-X2 antigen


Mass: 1134.200 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: P43358
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

Component
IDNameTypeEntity IDParent-IDSource
1HLA-A2 MAGEA4 (230-239) in complex with REGN6972 Fab and 2M2 FabCOMPLEXall0RECOMBINANT
2REGN6972 Fab light chain, REGN6972 Fab heavy chainCOMPLEX#1-#21RECOMBINANT
3MHC class I antigen, Beta-2-microglobulinCOMPLEX#3-#41RECOMBINANT
4Melanoma-associated antigen 4 peptideCOMPLEX#51SYNTHETIC
Molecular weightExperimental value: NO
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
12Homo sapiens (human)9606
23Homo sapiens (human)9606
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
12Cricetulus griseus (Chinese hamster)10029
23Escherichia coli (E. coli)562
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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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 defocus max: 2400 nm / Nominal defocus min: 1400 nm
Image recordingElectron dose: 40 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)
EM imaging opticsEnergyfilter name: GIF Bioquantum / Energyfilter slit width: 20 eV

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Processing

Software
NameVersionClassification
phenix.real_space_refine1.19.2_4158refinement
PHENIX1.19.2_4158refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 117411 / Symmetry type: POINT
RefinementCross valid method: NONE
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
Displacement parametersBiso mean: 102.41 Å2
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0076580
ELECTRON MICROSCOPYf_angle_d0.84138933
ELECTRON MICROSCOPYf_chiral_restr0.0512957
ELECTRON MICROSCOPYf_plane_restr0.00621157
ELECTRON MICROSCOPYf_dihedral_angle_d4.8651890

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