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Yorodumi- PDB-8vr9: Structure of a synthetic antibody in complex with a class I MHC p... -
+Open data
-Basic information
Entry | Database: PDB / ID: 8vr9 | ||||||
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Title | Structure of a synthetic antibody in complex with a class I MHC presenting a hapten-peptide conjugate | ||||||
Components |
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Keywords | IMMUNE SYSTEM / Complex / Synthetic antibody / MHC class I / covalently modified peptide | ||||||
Function / homology | Function and homology information forebrain astrocyte development / positive regulation of memory T cell activation / T cell mediated cytotoxicity directed against tumor cell target / TAP complex binding / negative regulation of epithelial cell differentiation / regulation of synaptic transmission, GABAergic / positive regulation of CD8-positive, alpha-beta T cell activation / CD8-positive, alpha-beta T cell activation / positive regulation of CD8-positive, alpha-beta T cell proliferation / Golgi medial cisterna ...forebrain astrocyte development / positive regulation of memory T cell activation / T cell mediated cytotoxicity directed against tumor cell target / TAP complex binding / negative regulation of epithelial cell differentiation / regulation of synaptic transmission, GABAergic / positive regulation of CD8-positive, alpha-beta T cell activation / CD8-positive, alpha-beta T cell activation / positive regulation of CD8-positive, alpha-beta T cell proliferation / Golgi medial cisterna / epithelial tube branching involved in lung morphogenesis / type I pneumocyte differentiation / CD8 receptor binding / Rac protein signal transduction / antigen processing and presentation of exogenous peptide antigen via MHC class I / positive regulation of Rac protein signal transduction / skeletal muscle cell differentiation / Signaling by RAS GAP mutants / Signaling by RAS GTPase mutants / Activation of RAS in B cells / endoplasmic reticulum exit site / RAS signaling downstream of NF1 loss-of-function variants / RUNX3 regulates p14-ARF / antigen processing and presentation of endogenous peptide antigen via MHC class I via ER pathway, TAP-dependent / TAP binding / SOS-mediated signalling / Activated NTRK3 signals through RAS / Activated NTRK2 signals through RAS / protection from natural killer cell mediated cytotoxicity / SHC1 events in ERBB4 signaling / Signalling to RAS / glial cell proliferation / SHC-related events triggered by IGF1R / Activated NTRK2 signals through FRS2 and FRS3 / beta-2-microglobulin binding / Estrogen-stimulated signaling through PRKCZ / SHC-mediated cascade:FGFR3 / MET activates RAS signaling / Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants / Signaling by PDGFRA extracellular domain mutants / SHC-mediated cascade:FGFR2 / PTK6 Regulates RHO GTPases, RAS GTPase and MAP kinases / T cell receptor binding / SHC-mediated cascade:FGFR4 / Signaling by FGFR4 in disease / detection of bacterium / Erythropoietin activates RAS / SHC-mediated cascade:FGFR1 / protein-membrane adaptor activity / positive regulation of glial cell proliferation / FRS-mediated FGFR3 signaling / Signaling by CSF3 (G-CSF) / Signaling by FLT3 ITD and TKD mutants / homeostasis of number of cells within a tissue / FRS-mediated FGFR2 signaling / FRS-mediated FGFR4 signaling / Signaling by FGFR3 in disease / p38MAPK events / Tie2 Signaling / FRS-mediated FGFR1 signaling / striated muscle cell differentiation / Signaling by FGFR2 in disease / GRB2 events in EGFR signaling / SHC1 events in EGFR signaling / EGFR Transactivation by Gastrin / Signaling by FLT3 fusion proteins / FLT3 Signaling / Signaling by FGFR1 in disease / Ras activation upon Ca2+ influx through NMDA receptor / GRB2 events in ERBB2 signaling / CD209 (DC-SIGN) signaling / NCAM signaling for neurite out-growth / SHC1 events in ERBB2 signaling / Downstream signal transduction / Constitutive Signaling by Overexpressed ERBB2 / Insulin receptor signalling cascade / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / small monomeric GTPase / positive regulation of ferrous iron binding / positive regulation of transferrin receptor binding / G protein activity / VEGFR2 mediated cell proliferation / negative regulation of receptor binding / DAP12 interactions / antigen processing and presentation of endogenous peptide antigen via MHC class I via ER pathway, TAP-independent / positive regulation of receptor binding / antigen processing and presentation of endogenous peptide antigen via MHC class Ib / early endosome lumen / Nef mediated downregulation of MHC class I complex cell surface expression / cellular response to iron ion / Endosomal/Vacuolar pathway / lumenal side of endoplasmic reticulum membrane / Antigen Presentation: Folding, assembly and peptide loading of class I MHC / FCERI mediated MAPK activation / Signaling by ERBB2 TMD/JMD mutants / RAF activation / Signaling by high-kinase activity BRAF mutants / cellular response to iron(III) ion / Constitutive Signaling by EGFRvIII / antigen processing and presentation of exogenous protein antigen via MHC class Ib, TAP-dependent Similarity search - Function | ||||||
Biological species | Homo sapiens (human) | ||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.06 Å | ||||||
Authors | Maso, L. / Bang, I. / Koide, S. | ||||||
Funding support | United States, 1items
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Citation | Journal: Proc Natl Acad Sci U S A / Year: 2024 Title: Molecular basis for antibody recognition of multiple drug-peptide/MHC complexes. Authors: Lorenzo Maso / Epsa Rajak / Injin Bang / Akiko Koide / Takamitsu Hattori / Benjamin G Neel / Shohei Koide / Abstract: The HapImmune platform exploits covalent inhibitors as haptens for creating major histocompatibility complex (MHC)-presented tumor-specific neoantigens by design, combining targeted therapies with ...The HapImmune platform exploits covalent inhibitors as haptens for creating major histocompatibility complex (MHC)-presented tumor-specific neoantigens by design, combining targeted therapies with immunotherapy for the treatment of drug-resistant cancers. A HapImmune antibody, R023, recognizes multiple sotorasib-conjugated KRAS(G12C) peptides presented by different human leukocyte antigens (HLAs). This high specificity to sotorasib, coupled with broad HLA-binding capability, enables such antibodies, when reformatted as T cell engagers, to potently and selectively kill sotorasib-resistant KRAS(G12C) cancer cells expressing different HLAs upon sotorasib treatment. The loosening of HLA restriction could increase the patient population that can benefit from this therapeutic approach. To understand the molecular basis for its unconventional binding capability, we used single-particle cryogenic electron microscopy to determine the structures of R023 bound to multiple sotorasib-peptide conjugates presented by different HLAs. R023 forms a pocket for sotorasib between the V and V domains, binds HLAs in an unconventional, angled way, with V making most contacts with them, and makes few contacts with the peptide moieties. This binding mode enables the antibody to accommodate different hapten-peptide conjugates and to adjust its conformation to different HLAs presenting hapten-peptides. Deep mutational scanning validated the structures and revealed distinct levels of mutation tolerance by sotorasib- and HLA-binding residues. Together, our structural information and sequence landscape analysis reveal key features for achieving MHC-restricted recognition of multiple hapten-peptide antigens, which will inform the development of next-generation therapeutic antibodies. | ||||||
History |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 8vr9.cif.gz | 125.5 KB | Display | PDBx/mmCIF format |
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PDB format | pdb8vr9.ent.gz | 92.6 KB | Display | PDB format |
PDBx/mmJSON format | 8vr9.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 8vr9_validation.pdf.gz | 1.4 MB | Display | wwPDB validaton report |
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Full document | 8vr9_full_validation.pdf.gz | 1.4 MB | Display | |
Data in XML | 8vr9_validation.xml.gz | 38.2 KB | Display | |
Data in CIF | 8vr9_validation.cif.gz | 54.6 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/vr/8vr9 ftp://data.pdbj.org/pub/pdb/validation_reports/vr/8vr9 | HTTPS FTP |
-Related structure data
Related structure data | 43478MC 8vraC 8vrbC M: map data used to model this data C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
-Assembly
Deposited unit |
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1 |
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-Components
-Protein , 2 types, 2 molecules AB
#1: Protein | Mass: 32047.309 Da / Num. of mol.: 1 / Fragment: extracellular domain Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: HLA-A, HLAA / Plasmid: pET28 / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: P04439 |
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#2: Protein | Mass: 11892.291 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: B2M, CDABP0092, HDCMA22P / Plasmid: pHFT2 / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: P61769 |
-Antibody , 2 types, 2 molecules DE
#4: Antibody | Mass: 23518.178 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Production host: Escherichia coli (E. coli) |
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#5: Antibody | Mass: 24034.822 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Production host: Escherichia coli (E. coli) |
-Protein/peptide / Non-polymers , 2 types, 2 molecules C
#3: Protein/peptide | Mass: 789.963 Da / Num. of mol.: 1 / Fragment: residues 8-16 / Mutation: G12C / Source method: obtained synthetically / Details: Cys12 conjugated to covalent inhibitor sotorasib / Source: (synth.) Homo sapiens (human) / References: UniProt: P01116 |
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#6: Chemical | ChemComp-MOV / |
-Details
Has ligand of interest | Y |
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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 |
-Sample preparation
Component |
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Molecular weight | Value: 0.0927 MDa / Experimental value: NO | ||||||||||||||||||||||||||||||
Source (natural) |
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Source (recombinant) |
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Buffer solution | pH: 7.4 | ||||||||||||||||||||||||||||||
Buffer component |
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Specimen | Conc.: 1.5 mg/ml / 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 R0.6/1 | ||||||||||||||||||||||||||||||
Vitrification | Instrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277 K |
-Electron microscopy imaging
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
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Microscopy | Model: FEI TITAN KRIOS |
Electron gun | Electron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM |
Electron lens | Mode: BRIGHT FIELD / Nominal magnification: 105000 X / Nominal defocus max: 2400 nm / Nominal defocus min: 900 nm / Cs: 2.7 mm |
Specimen holder | Cryogen: NITROGEN |
Image recording | Average exposure time: 2 sec. / Electron dose: 57.72 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) / Num. of grids imaged: 1 |
EM imaging optics | Energyfilter slit width: 20 eV |
-Processing
EM software |
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CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||
3D reconstruction | Resolution: 3.06 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 178888 / Symmetry type: POINT |