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- PDB-9pkv: HU-38 Fab with PRAME pMHC -

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Basic information

Entry
Database: PDB / ID: 9pkv
TitleHU-38 Fab with PRAME pMHC
Components
  • Beta-2-microglobulin
  • HU-38 Heavy Chain
  • HU-38 Light Chain
  • MHC class I antigen
  • PRAME peptide
  • VHH antibody
KeywordsPEPTIDE BINDING PROTEIN/IMMUNE SYSTEM / PRAME / pMHC / PEPTIDE BINDING PROTEIN / PEPTIDE BINDING PROTEIN-IMMUNE SYSTEM complex
Function / homology
Function and homology information


antigen processing and presentation of peptide antigen via MHC class I / early endosome lumen / Nef mediated downregulation of MHC class I complex cell surface expression / DAP12 interactions / T cell mediated cytotoxicity / Endosomal/Vacuolar pathway / Antigen Presentation: Folding, assembly and peptide loading of class I MHC / lumenal side of endoplasmic reticulum membrane / antigen processing and presentation of exogenous protein antigen via MHC class Ib, TAP-dependent / regulation of iron ion transport ...antigen processing and presentation of peptide antigen via MHC class I / early endosome lumen / Nef mediated downregulation of MHC class I complex cell surface expression / DAP12 interactions / T cell mediated cytotoxicity / Endosomal/Vacuolar pathway / Antigen Presentation: Folding, assembly and peptide loading of class I MHC / lumenal side of endoplasmic reticulum membrane / antigen processing and presentation of exogenous protein antigen via MHC class Ib, TAP-dependent / regulation of iron ion transport / cellular response to iron(III) ion / negative regulation of iron ion transport / negative regulation of forebrain neuron differentiation / response to molecule of bacterial origin / regulation of erythrocyte differentiation / 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 / multicellular organismal-level iron ion homeostasis / 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 / positive regulation of T cell mediated cytotoxicity / negative regulation of epithelial cell proliferation / cellular response to nicotine / MHC class II protein complex / positive regulation of receptor-mediated endocytosis / negative regulation of neurogenesis / specific granule lumen / antigen processing and presentation of exogenous peptide antigen via MHC class II / positive regulation of immune response / peptide antigen binding / recycling endosome membrane / phagocytic vesicle membrane / positive regulation of T cell activation / Interferon gamma signaling / Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell / T cell differentiation in thymus / 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 / negative regulation of neuron projection development / late endosome membrane / protein refolding / ER-Phagosome pathway / early endosome membrane / amyloid fibril formation / protein homotetramerization / intracellular iron ion homeostasis / learning or memory / endoplasmic reticulum lumen / Amyloid fiber formation / external side of plasma membrane / Golgi membrane / lysosomal membrane / focal adhesion / Neutrophil degranulation / SARS-CoV-2 activates/modulates innate and adaptive immune responses / Golgi apparatus / structural molecule activity / endoplasmic reticulum / protein homodimerization activity / : / extracellular exosome / extracellular region / membrane / identical protein binding / plasma membrane / cytosol
Similarity search - Function
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. ...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
Beta-2-microglobulin / MHC class I antigen
Similarity search - Component
Biological speciesHomo sapiens (human)
Lama glama (llama)
Mus musculus (house mouse)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.72 Å
AuthorsMortenson, D.E. / Yu, X.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: MAbs / Year: 2025
Title: Development of a PRAME pMHC targeted T cell engager for solid tumor therapy.
Authors: Katarzyna Skrzypczynska / Kristin Schimert / Heather Stephenson / In Kyoung Mah / David Mortenson / Kelli Boyd / Timothy Hardman / Nikolai Novikov / Elbert Seto / Sabrina Lu / Randy Yen / ...Authors: Katarzyna Skrzypczynska / Kristin Schimert / Heather Stephenson / In Kyoung Mah / David Mortenson / Kelli Boyd / Timothy Hardman / Nikolai Novikov / Elbert Seto / Sabrina Lu / Randy Yen / Brian Lee / Min Wang / Don Kang / Ying Huang / Xinchao Yu / Magdeleine Hung / Sheng Ding / Nathan Thomsen / Nicole Schirle Oakdale /
Abstract: Bispecific T cell engager (TCE) therapies have demonstrated transformative clinical success in the treatment of hematological cancers, but the lack of antigens that are sufficiently selective for ...Bispecific T cell engager (TCE) therapies have demonstrated transformative clinical success in the treatment of hematological cancers, but the lack of antigens that are sufficiently selective for malignant cells has hampered the success of TCEs in the solid-tumor space. To overcome the on-target, off-tumor toxicities that result from the expression of even low levels of tumor-associated antigens in healthy tissues, we sought to identify a TCE target with highly tumor-restricted expression patterns. Here, we characterize cancer-testes antigen Preferentially Expressed Antigen in Melanoma (PRAME) as a highly selective tumor antigen and identify a proteasomal degradation peptide PRAME (PRAME) presented in the context of major histocompatibility complex I (MHCI) as an attractive TCE target. We designed a TCR-mimic (TCRm) antibody screening cascade that prioritizes screening anti-PRAME pMHC binders in off-target T cell dependent cellular cytotoxicity assays in a potent TCE format, rather than relying solely on traditional pMHC binding assays, to determine specificity. Using this screening cascade, we discovered antibodies that selectively bind PRAME pMHC without over-recognition of off-target peptides or MHCI via a TCR-like binding geometry. We further solved the first structure of an anti-PRAME pMHC TCRm antibody in complex with PRAME/HLA-A *02:01 using cryo electron microscopy to confirm the TCRm antibody binds in a TCR-like binding geometry and specifically recognizes the PRAME peptide. By formatting these novel TCRm antibodies into potent TCEs, we demonstrate PRAME pMHC-specific killing of tumor cells, representing a new class of anti-PRAME pMHC biologics.
History
DepositionJul 14, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 1, 2025Provider: repository / Type: Initial release
Revision 1.0Oct 1, 2025Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Oct 1, 2025Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
Revision 1.0Oct 1, 2025Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Oct 1, 2025Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Oct 1, 2025Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Oct 1, 2025Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.1Apr 29, 2026Group: Data collection / Database references / Category: citation / citation_author / em_admin
Item: _citation.page_first / _citation.page_last ..._citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _em_admin.last_update
Revision 1.1Apr 29, 2026Data content type: EM metadata / Data content type: EM metadata / EM metadata / Group: Database references / Experimental summary / Data content type: EM metadata / EM metadata / EM metadata / Category: citation / citation_author / em_admin
Data content type: EM metadata / EM metadata ...EM metadata / EM metadata / EM metadata / EM metadata / EM metadata / EM metadata
Item: _citation.page_first / _citation.page_last ..._citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: MHC class I antigen
K: VHH antibody
P: PRAME peptide
H: HU-38 Heavy Chain
B: Beta-2-microglobulin
L: HU-38 Light Chain


Theoretical massNumber of molelcules
Total (without water)109,4486
Polymers109,4486
Non-polymers00
Water3,441191
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Protein , 2 types, 2 molecules AB

#1: Protein MHC class I antigen


Mass: 34359.895 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HLA-A / Production host: Escherichia coli (E. coli) / References: UniProt: Q8WLS4
#5: Protein Beta-2-microglobulin


Mass: 11879.356 Da / Num. of mol.: 1 / Fragment: UNP residues 21-119
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

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Antibody , 3 types, 3 molecules KHL

#2: Antibody VHH antibody


Mass: 13246.515 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Lama glama (llama) / Production host: Saccharomyces cerevisiae (brewer's yeast)
#4: Antibody HU-38 Heavy Chain


Mass: 25680.639 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Cell line (production host): expi293 / Production host: Homo sapiens (human)
#6: Antibody HU-38 Light Chain


Mass: 23287.822 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Cell line (production host): expi293 / Production host: Homo sapiens (human)

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Protein/peptide / Non-polymers , 2 types, 192 molecules P

#3: Protein/peptide PRAME peptide


Mass: 994.209 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human)
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 191 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestN
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

ComponentName: complex of HU38 Fab with PRAME pMHC and anti-Kappa VHH
Type: COMPLEX / Entity ID: #1-#6 / Source: MULTIPLE SOURCES
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Escherichia coli (E. coli)
Buffer solutionpH: 7.4
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 10 K

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: SPOT SCAN
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2000 nm / Nominal defocus min: 800 nm / Cs: 2.7 mm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

EM software
IDNameVersionCategory
1cryoSPARCparticle selection
2PHENIX1.21_5207model refinement
11cryoSPARCfinal Euler assignment
13cryoSPARC3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.72 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 553793 / Symmetry type: POINT

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