[English] 日本語

- PDB-9nnf: Cryo-EM structure of a de-novo designed binder NY1-B04 in complex... -
+
Open data
-
Basic information
Entry | Database: PDB / ID: 9nnf | |||||||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
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 | |||||||||||||||||||||
![]() |
| |||||||||||||||||||||
![]() | IMMUNE SYSTEM / De novo-designed pMHC binders / HLA | |||||||||||||||||||||
Function / homology | ![]() 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 / 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)![]() ![]() ![]() | |||||||||||||||||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.8 Å | |||||||||||||||||||||
![]() | Gharpure, A. / Fernandez-Quintero, M.L. / Ward, A.B. | |||||||||||||||||||||
Funding support | 1items
| |||||||||||||||||||||
![]() | ![]() Title: 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 |
|
-
Structure visualization
Structure viewer | Molecule: ![]() ![]() |
---|
-
Downloads & links
-
Download
PDBx/mmCIF format | ![]() | 106 KB | Display | ![]() |
---|---|---|---|---|
PDB format | ![]() | 78.6 KB | Display | ![]() |
PDBx/mmJSON format | ![]() | Tree view | ![]() | |
Others | ![]() |
-Validation report
Summary document | ![]() | 1.2 MB | Display | ![]() |
---|---|---|---|---|
Full document | ![]() | 1.2 MB | Display | |
Data in XML | ![]() | 26 KB | Display | |
Data in CIF | ![]() | 36.9 KB | Display | |
Arichive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 49573MC M: map data used to model this data C: citing same article ( |
---|---|
Similar structure data | Similarity search - Function & homology ![]() |
-
Links
-
Assembly
Deposited unit | ![]()
|
---|---|
1 |
|
-
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: ![]() ![]() |
---|---|
#2: Protein | Mass: 31951.316 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() Production 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.) ![]() Production 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 |
---|---|
EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
-
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 |
---|---|
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 |
-
Electron microscopy imaging
Microscopy | Model: TFS GLACIOS |
---|---|
Electron gun | Electron source: ![]() |
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) |
-
Processing
EM software |
| ||||||||||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
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 |
|