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- PDB-8vsj: Engineered peptide-specific binder in complex with HLA-DR1/CLIP -

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Basic information

Entry
Database: PDB / ID: 8vsj
TitleEngineered peptide-specific binder in complex with HLA-DR1/CLIP
Components
  • (HLA class II histocompatibility ...) x 2
  • Class-II-associated invariant chain peptide
  • Superantigen
  • c44H10 Fab heavy chain
  • c44H10 Fab light chain
KeywordsIMMUNE SYSTEM / complex / engineered protein
Function / homology
Function and homology information


negative regulation of peptide secretion / macrophage migration inhibitory factor signaling pathway / NOS2-CD74 complex / MHC class II protein binding, via antigen binding groove / antigen processing and presentation of endogenous antigen / positive regulation of dendritic cell antigen processing and presentation / negative regulation of T cell differentiation / macrophage migration inhibitory factor binding / positive regulation of macrophage migration inhibitory factor signaling pathway / protein trimerization ...negative regulation of peptide secretion / macrophage migration inhibitory factor signaling pathway / NOS2-CD74 complex / MHC class II protein binding, via antigen binding groove / antigen processing and presentation of endogenous antigen / positive regulation of dendritic cell antigen processing and presentation / negative regulation of T cell differentiation / macrophage migration inhibitory factor binding / positive regulation of macrophage migration inhibitory factor signaling pathway / protein trimerization / macrophage migration inhibitory factor receptor complex / positive regulation of cytokine-mediated signaling pathway / myeloid dendritic cell antigen processing and presentation / antigen processing and presentation of endogenous peptide antigen via MHC class II / T cell activation involved in immune response / autolysosome membrane / positive regulation of prostaglandin biosynthetic process / regulation of T-helper cell differentiation / T cell selection / positive regulation of type 2 immune response / positive regulation of CD4-positive, CD25-positive, alpha-beta regulatory T cell differentiation / host-mediated suppression of symbiont invasion / MHC class II receptor activity / negative thymic T cell selection / positive regulation of CD4-positive, alpha-beta T cell activation / MHC class II protein binding / antigen processing and presentation of peptide or polysaccharide antigen via MHC class II / negative regulation of mature B cell apoptotic process / positive regulation of kinase activity / positive regulation of memory T cell differentiation / CD4 receptor binding / positive regulation of monocyte differentiation / positive thymic T cell selection / vacuole / cytokine receptor activity / positive regulation of chemokine (C-X-C motif) ligand 2 production / positive regulation of neutrophil chemotaxis / prostaglandin biosynthetic process / positive regulation of macrophage cytokine production / positive regulation of T cell differentiation / regulation of macrophage activation / nitric-oxide synthase binding / transport vesicle membrane / negative regulation of intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator / antigen processing and presentation / Translocation of ZAP-70 to Immunological synapse / cytokine binding / Phosphorylation of CD3 and TCR zeta chains / negative regulation of DNA damage response, signal transduction by p53 class mediator / polysaccharide binding / immunoglobulin mediated immune response / : / Generation of second messenger molecules / immunological synapse / response to type II interferon / Co-inhibition by PD-1 / T cell receptor binding / positive regulation of chemokine production / positive regulation of B cell proliferation / multivesicular body / protein folding chaperone / MHC class II antigen presentation / lysosomal lumen / negative regulation of cell migration / trans-Golgi network membrane / positive regulation of interleukin-8 production / lumenal side of endoplasmic reticulum membrane / Cell surface interactions at the vascular wall / intracellular protein transport / peptide antigen assembly with MHC class II protein complex / MHC class II protein complex / clathrin-coated endocytic vesicle membrane / ER to Golgi transport vesicle membrane / antigen processing and presentation of exogenous peptide antigen via MHC class II / positive regulation of immune response / peptide antigen binding / positive regulation of T cell mediated cytotoxicity / positive regulation of interleukin-6 production / positive regulation of T cell activation / cognition / positive regulation of fibroblast proliferation / Interferon gamma signaling / MHC class II protein complex binding / endocytic vesicle membrane / late endosome membrane / late endosome / Downstream TCR signaling / amyloid-beta binding / positive regulation of protein phosphorylation / protein-containing complex assembly / early endosome membrane / adaptive immune response / positive regulation of canonical NF-kappaB signal transduction / positive regulation of viral entry into host cell / lysosome / positive regulation of ERK1 and ERK2 cascade / positive regulation of MAPK cascade / protein stabilization / endosome membrane / immune response
Similarity search - Function
Mycoplasma arthritidis-derived mitogen / Superantigen MAM / Mycoplasma arthritidis-derived mitogen, C-terminal / Mycoplasma arthritidis-derived mitogen / MHC class II-associated invariant chain, trimerisation / MHC class II-associated invariant chain/CLIP, MHC II-interacting / MHC class II-associated invariant chain / MHC class II-associated invariant chain, trimerisation domain superfamily / HLA class II histocompatibility antigen, gamma subunit / Class II MHC-associated invariant chain trimerisation domain ...Mycoplasma arthritidis-derived mitogen / Superantigen MAM / Mycoplasma arthritidis-derived mitogen, C-terminal / Mycoplasma arthritidis-derived mitogen / MHC class II-associated invariant chain, trimerisation / MHC class II-associated invariant chain/CLIP, MHC II-interacting / MHC class II-associated invariant chain / MHC class II-associated invariant chain, trimerisation domain superfamily / HLA class II histocompatibility antigen, gamma subunit / Class II MHC-associated invariant chain trimerisation domain / CLIP, MHC2 interacting / : / Thyroglobulin type-1 repeat signature. / Thyroglobulin type-1 / Thyroglobulin type-1 superfamily / Thyroglobulin type-1 repeat / Thyroglobulin type-1 domain profile. / Thyroglobulin type I repeats. / MHC class II, beta chain, N-terminal / Class II histocompatibility antigen, beta domain / Class II histocompatibility antigen, beta domain / MHC class II, alpha chain, N-terminal / Class II histocompatibility antigen, alpha domain / Class II histocompatibility antigen, alpha domain / MHC class II, alpha/beta chain, N-terminal / 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
HLA class II histocompatibility antigen DR beta chain / HLA class II histocompatibility antigen, DR alpha chain / HLA class II histocompatibility antigen gamma chain / Superantigen
Similarity search - Component
Biological speciesHomo sapiens (human)
Metamycoplasma arthritidis (bacteria)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.28 Å
AuthorsJude, K.M. / Yang, X. / Du, H. / Kassardjian, A. / Julien, J.-P. / Huang, P. / Garcia, K.C.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)r01gm147893 United States
CitationJournal: Nat Biotechnol / Year: 2024
Title: A general system for targeting MHC class II-antigen complex via a single adaptable loop.
Authors: Haotian Du / Jingjia Liu / Kevin M Jude / Xinbo Yang / Ying Li / Braxton Bell / Hongli Yang / Audrey Kassardjian / Wyatt Blackson / Ali Mobedi / Udit Parekh / R Andres Parra Sperberg / Jean- ...Authors: Haotian Du / Jingjia Liu / Kevin M Jude / Xinbo Yang / Ying Li / Braxton Bell / Hongli Yang / Audrey Kassardjian / Wyatt Blackson / Ali Mobedi / Udit Parekh / R Andres Parra Sperberg / Jean-Philippe Julien / Elizabeth D Mellins / K Christopher Garcia / Po-Ssu Huang /
Abstract: Major histocompatibility complex class II (MHCII) bound to a peptide antigen mediates interactions between CD4 T cells and antigen-presenting cells. Targeting peptide-MHCII with T cell antigen ...Major histocompatibility complex class II (MHCII) bound to a peptide antigen mediates interactions between CD4 T cells and antigen-presenting cells. Targeting peptide-MHCII with T cell antigen receptors (TCRs) and TCR-like antibodies has shown promise for autoimmune diseases and microbiome tolerance. To develop a general targeting approach, we introduce targeted recognition of antigen-MHC complex reporter for MHCII (TRACeR-II) for the rapid development of peptide-specific MHCII binders. TRACeR-II binders have a small helical bundle scaffold and use a single loop to recognize peptide-MHCII, which offers versatility and enables structural modeling of the interactions to target MHCII antigens. We demonstrate rapid generation of TRACeR-II binders to multiple molecules with affinities in the low-nanomolar to low-micromolar range, comparable to best-in-class TCRs and antibodies. Through computational protein design, we created specific binding sequences in silico from only the sequence of a severe acute respiratory syndrome coronavirus 2 peptide. TRACeR-II provides a straightforward approach to target antigen-MHCII without relying on combinatorial selection on complementarity-determining region loops.
History
DepositionJan 24, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 2, 2024Provider: repository / Type: Initial release
Revision 1.1Oct 23, 2024Group: Data collection / Structure summary
Category: em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _em_admin.last_update / _pdbx_entry_details.has_protein_modification
Revision 1.2Feb 19, 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_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _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
A: HLA class II histocompatibility antigen, DR alpha chain
B: HLA class II histocompatibility antigen DR beta chain
C: Superantigen
H: c44H10 Fab heavy chain
L: c44H10 Fab light chain
P: Class-II-associated invariant chain peptide
hetero molecules


Theoretical massNumber of molelcules
Total (without water)108,7839
Polymers108,1206
Non-polymers6643
Water00
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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HLA class II histocompatibility ... , 2 types, 2 molecules AB

#1: Protein HLA class II histocompatibility antigen, DR alpha chain / MHC class II antigen DRA


Mass: 21400.178 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HLA-DRA, HLA-DRA1 / Production host: Homo sapiens (human) / References: UniProt: P01903
#2: Protein HLA class II histocompatibility antigen DR beta chain / HLA-DRB1 protein / MHC class II antigen


Mass: 22324.938 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HLA-DRB1 / Production host: Homo sapiens (human) / References: UniProt: D7RIG0

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Antibody , 2 types, 2 molecules HL

#4: Antibody c44H10 Fab heavy chain


Mass: 23668.643 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human)
#5: Antibody c44H10 Fab light chain


Mass: 23505.068 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human)

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Protein / Protein/peptide / Sugars , 3 types, 5 molecules CP

#3: Protein Superantigen


Mass: 15544.818 Da / Num. of mol.: 1
Mutation: V30C, Q37S, K38I, H39Y, F40L, V41A, Y59D, L72K, L75E, G86D, V88I, D90K, N92G, G93D, delta 94-97, I100V, T110I, I127T, S144C
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Metamycoplasma arthritidis (bacteria) / Production host: Escherichia coli (E. coli) / References: UniProt: Q48898
#6: Protein/peptide Class-II-associated invariant chain peptide / CLIP


Mass: 1676.118 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CD74, DHLAG / Production host: Homo sapiens (human) / References: UniProt: P04233
#7: Sugar ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C8H15NO6
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0

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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: Engineered peptide-specific binder in complex with HLA-DR1/CLIP
Type: COMPLEX / Entity ID: #1-#6 / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.3
Buffer component
IDConc.NameFormulaBuffer-ID
10.15 Msodium chlorideNaCl1
20.01 MHEPES1
30.01 %fluorinated octylmaltoside1
SpecimenConc.: 2 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 4 K

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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 magnification: 165000 X / Nominal defocus max: 1800 nm / Nominal defocus min: 800 nm / Cs: 2.7 mm / C2 aperture diameter: 50 µm / Alignment procedure: COMA FREE
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 60 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k) / Num. of grids imaged: 1 / Num. of real images: 21332 / Details: eer images

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Processing

EM softwareName: PHENIX / Version: 1.21_5207 / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 18639350 / Details: template based picks
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 2.28 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 3706646 / Num. of class averages: 1 / Symmetry type: POINT
RefinementCross valid method: NONE
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
Displacement parametersBiso mean: 77.98 Å2
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00225967
ELECTRON MICROSCOPYf_angle_d0.44698082
ELECTRON MICROSCOPYf_chiral_restr0.0397887
ELECTRON MICROSCOPYf_plane_restr0.00361037
ELECTRON MICROSCOPYf_dihedral_angle_d11.71472243

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