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6L9M

H2-Ld binding "SPSYVYHQF" at 2.60Å resolution

Data provenance

Structure downloaded from PDB Europe using the Coordinate Server. Aligned to residues 1-180 of 1HHK2 using the CEALIGN3 function of PyMol4. Chain assigment using a Levenshtein distance5 method using data from the PDBe REST API6. Organism data from PDBe REST API. Data for both of these operations from the Molecules endpoint. Structure visualised with 3DMol7.

Information sections


Complex type

Class i with peptide

1. Beta 2 microglobulin
['B', 'E', 'H', 'K']
2. Class I alpha
H2-Ld
['A', 'D', 'G', 'J']
3. Peptide
SPSYVYHQF
['C', 'F', 'I', 'L']

Species


Locus / Allele group


Publication

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

Wei P, Jordan KR, Buhrman JD, Lei J, Deng H, Marrack P, Dai S, Kappler JW, Slansky JE, Yin L
Proc Natl Acad Sci U S A (2021) 118, [doi:10.1073/pnas.2100588118]  [pubmed:34074778

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.

Structure deposition and release

Deposited: 2019-11-10
Released: 2020-11-18
Revised: 2021-06-16

Data provenance

Publication data retrieved from PDBe REST API8 and PMCe REST API9

Other structures from this publication


Peptide details

Length: Nonamer (9 amino acids)

Sequence: SPSYVYHQF

Interactive view
Cutaway side view (static)
Surface top view (static - coloured by atom property)
Cutaway top view (static)

Data provenance

MHC:peptide complexes are visualised using PyMol. The peptide is superimposed on a consistent cutaway slice of the MHC binding cleft (displayed as a grey mesh) which best indicates the binding pockets for the P1/P5/PC positions (side view - pockets A, E, F) and for the P2/P3/PC-2 positions (top view - pockets B, C, D). In some cases peptides will use a different pocket for a specific peptide position (atypical anchoring). On some structures the peptide may appear to sterically clash with a pocket. This is an artefact of picking a standardised slice of the cleft and overlaying the peptide.


Peptide neighbours

P1 SER

ILE66
TYR171
TRP167
TYR99
TYR159
TYR7
TYR59
MET5
ARG62
ILE63
P2 PRO

SER24
ILE63
ILE66
TYR99
TYR159
TYR7
TYR45
GLU9
P3 SER

TYR159
TRP97
GLU9
GLN70
ILE66
TYR99
P4 TYR

GLN65
ILE66
TYR156
GLN70
TYR155
GLY69
TRP97
P5 VAL

TRP73
TRP97
TRP147
TYR156
GLN70
TYR155
PHE116
P6 TYR

TYR156
GLN70
TYR155
TRP73
P7 HIS

ALA152
TYR156
TYR155
TRP73
ASN77
TRP147
GLY151
ALA150
P8 GLN

VAL76
LYS146
TRP73
ASN77
TRP147
THR143
P9 PHE

ILE142
TYR84
THR143
LYS146
ILE124
TRP73
PHE116
TYR123
THR80
LEU81
TRP147
LEU95
ASN77

Colour key

Aromatic Hydrophobic Acidic Basic Neutral/polar

Data provenance

Neighbours are calculated by finding residues with atoms within 5Å of each other using BioPython Neighboursearch module. The list of neighbours is then sorted and filtered to inlcude only neighbours where between the peptide and the MHC Class I alpha chain.

Colours selected to match the YRB scheme. [https://www.frontiersin.org/articles/10.3389/fmolb.2015.00056/full]


Binding cleft pockets


Peptide sidechain binding pockets (static)
Peptide terminii and backbone binding residues (static)
A Pocket

ALA159
GLY163
GLU167
ARG171
SER5
GLU59
ARG63
GLN66
ARG7
B Pocket

ILE24
PHE34
ARG45
ARG63
GLN66
ILE67
ARG7
GLY70
PHE9
MET99
C Pocket

GLY70
GLN73
TRP74
PHE9
GLN97
D Pocket

TYR114
GLU155
TYR156
ALA159
TYR160
MET99
E Pocket

TYR114
LYS147
GLY152
TYR156
GLN97
F Pocket

GLN116
ASP123
ILE143
ARG146
LYS147
VAL77
ARG80
THR81
GLY84
THR95

Colour key

Binds N-terminus Binds P1 backbone Binds P2 backbone Binds PC-1 backbone Binds C-terminus

Data provenance

N-/C-terminus and peptide backbone binding residues are assigned according to previously published information and pockets are assigned according to an adaptation of a previously published set of residues. All numbering is currently that of the 'canonical' structures of human and mouse MHC Class I molecules.

Chain sequences

1. Beta 2 microglobulin
Beta 2 microglobulin
        10        20        30        40        50        60
IQKTPQIQVYSRHPPENGKPNILNCYVTQFHPPHIEIQMLKNGKKIPKVEMSDMSFSKDW
        70        80        90
SFYILAHTEFTPTETDTYACRVKHDSMAEPKTVYWDRDM

2. Class I alpha
H2-Ld
        10        20        30        40        50        60
AGPHSMRYFETAVSRPGLGEPRYISVGYVDNKEFVRFDSDAENPRYEPQAPWMEQEGPEY
        70        80        90       100       110       120
WERITQIAKGQEQWFRVNLRTLLGYYNQSAGGTHTLQWMYGCDVGSDGRLLRGYEQFAYD
       130       140       150       160       170       180
GCDYIALNEDLKTWTAADMAAQITRRKWEQAGAAEYYRAYLEGECVEWLHRYLKNGNATL
       190       200       210       220       230       240
LRTDSPKAHVTHHPRSKGEVTLRCWALGFYPADITLTWQLNGEELTQDMELVETRPAGDG
       250       260       270
TFQKWASVVVPLGKEQNYTCRVYHEGLPEPLTLRWEPP

3. Peptide
SPSYVYHQF


Data provenance

Sequences are retrieved via the Uniprot method of the RSCB REST API. Sequences are then compared to those derived from the PDB file and matched against sequences retrieved from the IPD-IMGT/HLA database for human sequences, or the IPD-MHC database for other species. Mouse sequences are matched against FASTA files from Uniprot. Sequences for the mature extracellular protein (signal petide and cytoplasmic tail removed) are compared to identical length sequences from the datasources mentioned before using either exact matching or Levenshtein distance based matching.


Downloadable data

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or in the case of JSON formatted files to retrieve it and use it as part of notebooks such as Jupyter or GoogleColab.
Please take note of the data license. Using data from this site assumes that you have read and will comply with the license.

Complete structures

Aligned structures [cif]
  1. 6L9M assembly 1  
  2. 6L9M assembly 2  
  3. 6L9M assembly 3  
  4. 6L9M assembly 4  

Components

MHC Class I alpha chain [cif]
  1. 6L9M assembly 1  
  2. 6L9M assembly 2  
  3. 6L9M assembly 3  
  4. 6L9M assembly 4  
MHC Class I antigen binding domain (alpha1/alpha2) [cif]
  1. 6L9M assembly 1  
  2. 6L9M assembly 2  
  3. 6L9M assembly 3  
  4. 6L9M assembly 4  
Peptide only [cif]
  1. 6L9M assembly 1  
  2. 6L9M assembly 2  
  3. 6L9M assembly 3  
  4. 6L9M assembly 4  

Derived data

Data for this page [json]
https://api.histo.fyi/v1/structures/6l9m

Data license

The data above is made available under a Creative Commons CC-BY 4.0 license. This means you can copy, remix, transform, build upon and redistribute the material, but you must give appropriate credit, provide a link to the license, and indicate if changes were made.
If you use any data downloaded from this site in a publication, please cite 'https://www.histo.fyi/'. A preprint is in preparation.

Footnotes