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Yorodumi- PDB-9nnf: Cryo-EM structure of a de-novo designed binder NY1-B04 in complex... -
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Open data
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Basic information
| Entry | Database: PDB / ID: 9nnf | |||||||||||||||||||||
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| Title | Cryo-EM structure of a de-novo designed binder NY1-B04 in complex with HLA-A*02:01 and NY-ESO-1-derived peptide SLLMWITQC | |||||||||||||||||||||
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Keywords | IMMUNE SYSTEM / De novo-designed pMHC binders / HLA | |||||||||||||||||||||
| Function / homology | Function and homology informationantigen 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 / 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 / ER to Golgi transport vesicle membrane / peptide antigen assembly with MHC class I protein complex / regulation of iron ion transport / regulation of erythrocyte differentiation / HFE-transferrin receptor complex / response to molecule of bacterial origin / MHC class I peptide loading complex / T cell mediated cytotoxicity / positive regulation of T cell cytokine production / antigen processing and presentation of endogenous peptide antigen via MHC class I / 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 / cellular response to nicotine / positive regulation of T cell mediated cytotoxicity / multicellular organismal-level iron ion homeostasis / specific granule lumen / phagocytic vesicle membrane / recycling endosome membrane / Interferon gamma signaling / Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell / negative regulation of epithelial cell proliferation / MHC class II protein complex binding / Modulation by Mtb of host immune system / late endosome membrane / sensory perception of smell / positive regulation of cellular senescence / tertiary granule lumen / DAP12 signaling / T cell differentiation in thymus / negative regulation of neuron projection development / ER-Phagosome pathway / protein refolding / early endosome membrane / protein homotetramerization / amyloid fibril formation / intracellular iron ion homeostasis / learning or memory / immune response / endoplasmic reticulum lumen / Amyloid fiber formation / 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 / Golgi apparatus / protein homodimerization activity / extracellular space / extracellular exosome / extracellular region / metal ion binding / identical protein binding / membrane / plasma membrane / cytosol Similarity search - Function | |||||||||||||||||||||
| Biological species | synthetic construct (others) Homo sapiens (human)![]() | |||||||||||||||||||||
| Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.8 Å | |||||||||||||||||||||
Authors | Gharpure, A. / Fernandez-Quintero, M.L. / Ward, A.B. | |||||||||||||||||||||
| Funding support | 1items
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Citation | Journal: Science / Year: 2025Title: De novo-designed pMHC binders facilitate T cell-mediated cytotoxicity toward cancer cells. Authors: Kristoffer Haurum Johansen / Darian Stephan Wolff / Beatrice Scapolo / Monica L Fernández-Quintero / Charlotte Risager Christensen / Johannes R Loeffler / Esperanza Rivera-de-Torre / Max D ...Authors: Kristoffer Haurum Johansen / Darian Stephan Wolff / Beatrice Scapolo / Monica L Fernández-Quintero / Charlotte Risager Christensen / Johannes R Loeffler / Esperanza Rivera-de-Torre / Max D Overath / Kamilla Kjærgaard Munk / Oliver Morell / Marie Christine Viuff / Iñigo Lacunza / Alberte T Damm Englund / Mathilde Due / Anant Gharpure / Stefano Forli / Carlos Rodriguez Pardo / Tripti Tamhane / Emma Qingjie Andersen / Kasper Haldrup Björnsson / Jordan Sylvester Fernandes / Lasse Frank Voss / Suthimon Thumtecho / Andrew B Ward / Maria Ormhøj / Sine Reker Hadrup / Timothy P Jenkins / ![]() Abstract: The recognition of intracellular antigens by CD8 T cells through T cell receptors (TCRs) is central for adaptive immunity against infections and cancer. However, the identification of TCRs from ...The recognition of intracellular antigens by CD8 T cells through T cell receptors (TCRs) is central for adaptive immunity against infections and cancer. However, the identification of TCRs from patient material remains complex. We present a rapid de novo minibinder (miBd) design platform leveraging state-of-the-art generative models to engineer miBds targeting the cancer-associated peptide-bound major histocompatibility complex (pMHC) SLLMWITQC/HLA-A*02:01 (NY-ESO-1). Incorporating in silico cross-panning enabled computational prescreening of specificity, and molecular dynamics simulations allowed for improved predictability of in vitro success. We identified a high-affinity NY-ESO-1 binder and confirmed its structure using cryo-electron microscopy, which, when incorporated in a chimeric antigen receptor, induced killing of NY-ESO-1 melanoma cells. We further designed and validated binders to a neoantigen pMHC complex, RVTDESILSY/HLA-A*01:01, with unknown structure, demonstrating the potential for precision immunotherapy. | |||||||||||||||||||||
| History |
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Structure visualization
| Structure viewer | Molecule: Molmil Jmol/JSmol |
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Downloads & links
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Download
| PDBx/mmCIF format | 9nnf.cif.gz | 106 KB | Display | PDBx/mmCIF format |
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| PDB format | pdb9nnf.ent.gz | 78.6 KB | Display | PDB format |
| PDBx/mmJSON format | 9nnf.json.gz | Tree view | PDBx/mmJSON format | |
| Others | Other downloads |
-Validation report
| Summary document | 9nnf_validation.pdf.gz | 1.2 MB | Display | wwPDB validaton report |
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| Full document | 9nnf_full_validation.pdf.gz | 1.2 MB | Display | |
| Data in XML | 9nnf_validation.xml.gz | 26 KB | Display | |
| Data in CIF | 9nnf_validation.cif.gz | 36.9 KB | Display | |
| Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/nn/9nnf ftp://data.pdbj.org/pub/pdb/validation_reports/nn/9nnf | HTTPS FTP |
-Related structure data
| Related structure data | ![]() 49573MC M: map data used to model this data C: citing same article ( |
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| Similar structure data | Similarity search - Function & homology F&H Search |
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Links
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Assembly
| Deposited unit | ![]()
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Components
| #1: Protein | Mass: 15054.265 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) synthetic construct (others) / Production host: ![]() |
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| #2: Protein | Mass: 31951.316 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: HLA-AProduction host: ![]() References: UniProt: Q861F7 |
| #3: Protein | 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, HDCMA22PProduction host: ![]() References: UniProt: P61769 |
| #4: Protein/peptide | Mass: 1094.347 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() |
| Has protein modification | Y |
-Experimental details
-Experiment
| Experiment | Method: ELECTRON MICROSCOPY |
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| EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
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Sample preparation
| Component | Name: de-novo designed binder NY1-B04 in complex with HLA-A*02:01 and NY-ESO-1-derived peptide SLLMWITQC Type: COMPLEX / Entity ID: all / Source: RECOMBINANT |
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| Molecular weight | Value: 58 kDa/nm / Experimental value: NO |
| Source (natural) | Organism: ![]() |
| Source (recombinant) | Organism: ![]() |
| Buffer solution | pH: 7.4 |
| Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES |
| Specimen support | Grid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R1.2/1.3 |
| Vitrification | Cryogen name: ETHANE |
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Electron microscopy imaging
| Microscopy | Model: TFS GLACIOS |
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| Electron gun | Electron source: FIELD EMISSION GUN / Accelerating voltage: 200 kV / Illumination mode: FLOOD BEAM |
| Electron lens | Mode: DIFFRACTION / Nominal defocus max: 2000 nm / Nominal defocus min: 900 nm / Cs: 2.7 mm / C2 aperture diameter: 50 µm |
| Image recording | Electron dose: 59.82 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k) |
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Processing
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| CTF correction | Type: NONE | ||||||||||||||||||||||||
| Particle selection | Num. of particles selected: 343587 Details: two collections one with and one without tilt resulted in 1627079 + 1808795 particles | ||||||||||||||||||||||||
| 3D reconstruction | Resolution: 3.8 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 106421 / Symmetry type: POINT | ||||||||||||||||||||||||
| Refinement | Highest resolution: 3.8 Å Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS) | ||||||||||||||||||||||||
| Refine LS restraints |
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Homo sapiens (human)

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FIELD EMISSION GUN