6L9M

H2-Ld complexed with AH1 peptide

  • Classification: IMMUNE SYSTEM
  • Organism(s): Homo sapiens
  • Expression System: Escherichia coli, synthetic construct
  • Mutation(s): No 

  • Deposited: 2019-11-10 Released: 2020-11-18 
  • Deposition Author(s): Wei, P.C., Yin, L.
  • Funding Organization(s): National Natural Science Foundation of China (NSFC), National Basic Research Program of China (973 Program), National Institutes of Health/Office of the Director

Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.60 Å
  • R-Value Free: 0.249 
  • R-Value Work: 0.213 
  • R-Value Observed: 0.214 

wwPDB Validation   3D Report Full Report


This is version 3.2 of the entry. See complete history


Literature

Structures suggest an approach for converting weak self-peptide tumor antigens into superagonists for CD8 T cells in cancer.

Wei, P.Jordan, K.R.Buhrman, J.D.Lei, J.Deng, H.Marrack, P.Dai, S.Kappler, J.W.Slansky, J.E.Yin, L.

(2021) Proc Natl Acad Sci U S A 118

  • DOI: https://doi.org/10.1073/pnas.2100588118
  • Primary Citation of Related Structures:  
    6L9K, 6L9L, 6L9M, 6L9N

  • PubMed Abstract: 

    Tumors frequently express unmutated self-tumor-associated antigens (self-TAAs). However, trial results using self-TAAs as vaccine targets against cancer are mixed, often attributed to deletion of T cells with high-affinity receptors (TCRs) for self-TAAs during T cell development. Mutating these weak self-TAAs to produce higher affinity, effective vaccines is challenging, since the mutations may not benefit all members of the broad self-TAA-specific T cell repertoire. We previously identified a common weak murine self-TAA that we converted to a highly effective antitumor vaccine by a single amino acid substitution. In this case the modified and natural self-TAAs still raised very similar sets of CD8 T cells. Our structural studies herein show that the modification of the self-TAA resulted in a subtle change in the major histocompatibility complex I-TAA structure. This amino acid substitution allowed a dramatic conformational change in the peptide during subsequent TCR engagement, creating a large increase in TCR affinity and accounting for the efficacy of the modified self-TAA as a vaccine. These results show that carefully selected, well-characterized modifications to a poorly immunogenic self-TAA can rescue the immune response of the large repertoire of weakly responding natural self-TAA-specific CD8 T cells, driving them to proliferate and differentiate into functional effectors. Subsequently, the unmodified self-TAA on the tumor cells, while unable to drive this response, is nevertheless a sufficient target for the CD8 cytotoxic effectors. Our results suggest a pathway for more efficiently identifying variants of common self-TAAs, which could be useful in vaccine development, complementing other current nonantigen-specific immunotherapies.


  • Organizational Affiliation

    Key Laboratory of Virology, Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, 430072 Wuhan, China.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
H2-Ld
A, D, G, J
278Homo sapiensMutation(s): 0 
UniProt
Find proteins for P01897 (Mus musculus)
Explore P01897 
Go to UniProtKB:  P01897
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP01897
Sequence Annotations
Expand
  • Reference Sequence
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
b2m
B, E, H, K
99Homo sapiensMutation(s): 0 
UniProt & NIH Common Fund Data Resources
Find proteins for P01887 (Mus musculus)
Explore P01887 
Go to UniProtKB:  P01887
IMPC:  MGI:88127
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP01887
Sequence Annotations
Expand
  • Reference Sequence

Find similar proteins by:  Sequence   |   3D Structure  

Entity ID: 3
MoleculeChains Sequence LengthOrganismDetailsImage
SER-PRO-SER-TYR-VAL-TYR-HIS-GLN-PHE
C, F, I, L
9Homo sapiensMutation(s): 0 
Sequence Annotations
Expand
  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.60 Å
  • R-Value Free: 0.249 
  • R-Value Work: 0.213 
  • R-Value Observed: 0.214 
  • Space Group: P 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 51.865α = 80.97
b = 88.39β = 75.96
c = 105.71γ = 88.24
Software Package:
Software NamePurpose
PHENIXrefinement
PDB_EXTRACTdata extraction
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing

Structure Validation

View Full Validation Report



Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
National Natural Science Foundation of China (NSFC)China3187072
National Natural Science Foundation of China (NSFC)China31470738
National Basic Research Program of China (973 Program)China2014CB910103
National Institutes of Health/Office of the DirectorUnited States1R01CA226879-01

Revision History  (Full details and data files)

  • Version 1.0: 2020-11-18
    Type: Initial release
  • Version 2.0: 2021-03-24
    Changes: Advisory, Atomic model, Data collection, Database references, Derived calculations, Structure summary
  • Version 3.0: 2021-04-07
    Type: Coordinate replacement
    Reason: Sequence discrepancy
    Changes: Atomic model, Author supporting evidence, Data collection, Database references, Derived calculations, Polymer sequence, Refinement description, Structure summary
  • Version 3.1: 2021-06-16
    Changes: Database references
  • Version 3.2: 2023-11-22
    Changes: Advisory, Data collection, Database references, Refinement description