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- PDB-8t6m: Human leukocyte antigen bound by two alloreactive antibody Fabs -

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Basic information

Entry
Database: PDB / ID: 8t6m
TitleHuman leukocyte antigen bound by two alloreactive antibody Fabs
Components
  • Beta-2-microglobulin
  • HLA_A0101_peptide
  • JTK191b_L02_Fab
  • JTK191b_L02_Light
  • JTK191b_M07_Fab
  • JTK191b_M07_Light
  • MHC class I antigen
KeywordsIMMUNE SYSTEM / antibody / human leukocyte antigen / graft rejection
Function / homology
Function and homology information


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 / 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 ...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 / 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 / negative regulation of forebrain neuron differentiation / MHC class II protein complex / 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 / peptide antigen binding / positive regulation of T cell activation / negative regulation of neurogenesis / positive regulation of receptor-mediated endocytosis / 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 / endoplasmic reticulum lumen / Amyloid fiber formation / Golgi membrane / external side of plasma membrane / lysosomal membrane / focal adhesion / Neutrophil degranulation / SARS-CoV-2 activates/modulates innate and adaptive immune responses / structural molecule activity / endoplasmic reticulum / Golgi apparatus / protein homodimerization activity / extracellular space / extracellular exosome / extracellular region / identical protein binding / membrane / 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
MHC class I antigen / Beta-2-microglobulin
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.14 Å
AuthorsKizziah, J.L. / Killian, J.T. / Diaz-Avalos, R. / Qiu, S. / Yang, G. / Green, T. / Lund, F.E.
Funding support United States, 5items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Disease (NIH/NIDDK)T32DK007545 United States
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)T32AI007051 United States
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)U19AI142737 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)S10OD024978 United States
National Institutes of Health/National Cancer Institute (NIH/NCI)P30CA013148 United States
CitationJournal: Immunity / Year: 2025
Title: Topography of the HLA-A protein enforces shared and convergent immunodominant B cell and antibody alloresponses in transplant recipients.
Authors: John T Killian / R Glenn King / Aaron C K Lucander / James L Kizziah / Christopher F Fucile / Ruben Diaz-Avalos / Shihong Qiu / Aaron Silva-Sanchez / Betty J Mousseau / Kevin J Macon / ...Authors: John T Killian / R Glenn King / Aaron C K Lucander / James L Kizziah / Christopher F Fucile / Ruben Diaz-Avalos / Shihong Qiu / Aaron Silva-Sanchez / Betty J Mousseau / Kevin J Macon / Amanda R Callahan / Guang Yang / M Emon Hossain / Jobaida Akther / Daryl B Good / Susan Kelso / Julie A Houp / Frida Rosenblum / Paige M Porrett / Song C Ong / Vineeta Kumar / Erica Ollmann Saphire / John F Kearney / Troy D Randall / Alexander F Rosenberg / Todd J Green / Frances E Lund /
Abstract: Donor-specific antibody responses against human leukocyte antigen (HLA) proteins mismatched between transplant donors and recipients cause allograft loss, yet the structural HLA epitopes targeted by ...Donor-specific antibody responses against human leukocyte antigen (HLA) proteins mismatched between transplant donors and recipients cause allograft loss, yet the structural HLA epitopes targeted by alloreactive B cells and antibodies remain largely unresolved. We profiled the HLA-A01:01-specific B cell response in the transplanted kidney and blood of a recipient undergoing antibody-mediated rejection and identified immunodominant B cell and antibody responses that emerged early in the alloimmune response. These responses were focused on topographically exposed mismatched HLA residues located in the α helices along the peptide-binding groove of HLA-A01:01. We demonstrated that the anti-HLA-A01:01 B cell alloresponse converged and was maintained on this same immunodominant HLA subregion, which comprises only 20% of the HLA molecule, in a diverse group of HLA-A01:01-mismatched transplant recipients. Thus, the B cell and antibody alloresponses appear tightly focused on a topographically defined region on the HLA-A01:01 crown that is conserved across individuals expressing distinct constellations of self-HLA-A.
History
DepositionJun 16, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 25, 2024Provider: repository / Type: Initial release
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: JTK191b_M07_Light
B: JTK191b_M07_Fab
C: JTK191b_L02_Light
D: JTK191b_L02_Fab
E: MHC class I antigen
F: Beta-2-microglobulin
G: HLA_A0101_peptide


Theoretical massNumber of molelcules
Total (without water)128,8607
Polymers128,8607
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Protein , 2 types, 2 molecules EF

#5: Protein MHC class I antigen


Mass: 20992.166 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HLA-A / Production host: Homo sapiens (human) / References: UniProt: I3QHR3
#6: 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: Homo sapiens (human) / References: UniProt: P61769

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Protein/peptide , 1 types, 1 molecules G

#7: Protein/peptide HLA_A0101_peptide


Mass: 1091.191 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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Antibody , 4 types, 4 molecules ABCD

#1: Antibody JTK191b_M07_Light


Mass: 23514.057 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human)
#2: Antibody JTK191b_M07_Fab


Mass: 24290.279 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human)
#3: Antibody JTK191b_L02_Light


Mass: 23352.977 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human)
#4: Antibody JTK191b_L02_Fab


Mass: 23739.482 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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Details

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: L02/M07/A*01:01 complex / Type: COMPLEX / Entity ID: all / Source: NATURAL
Source (natural)Organism: Homo sapiens (human)
Buffer solutionpH: 7.4
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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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 defocus max: 2200 nm / Nominal defocus min: 600 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.14 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 252746 / Symmetry type: POINT

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