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6UK4

HLA-A*02:06 presenting "KQWLVWLFL" to Alpha/Beta T cell receptor at 2.70Å 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 and alpha beta tcr

1. Beta 2 microglobulin
['B']
2. Class I alpha
HLA-A*02:06
['A']
3. Peptide
KQWLVWLFL
['C']
4. T cell receptor alpha
TRAV38
['D']
5. T cell receptor beta
TRBV12
['E']

Species


Locus / Allele group


Publication

Structural dissimilarity from self drives neoepitope escape from immune tolerance.

Devlin JR, Alonso JA, Ayres CM, Keller GLJ, Bobisse S, Vander Kooi CW, Coukos G, Gfeller D, Harari A, Baker BM
Nat. Chem. Biol. (2020) [doi:10.1038/s41589-020-0610-1]  [pubmed:32807968

T-cell recognition of peptides incorporating nonsynonymous mutations, or neoepitopes, is a cornerstone of tumor immunity and forms the basis of new immunotherapy approaches including personalized cancer vaccines. Yet as they are derived from self-peptides, the means through which immunogenic neoepitopes overcome immune self-tolerance are often unclear. Here we show that a point mutation in a non-major histocompatibility complex anchor position induces structural and dynamic changes in an immunologically active ovarian cancer neoepitope. The changes pre-organize the peptide into a conformation optimal for recognition by a neoepitope-specific T-cell receptor, allowing the receptor to bind the neoepitope with high affinity and deliver potent T-cell signals. Our results emphasize the importance of structural and physical changes relative to self in neoepitope immunogenicity. Considered broadly, these findings can help explain some of the difficulties in identifying immunogenic neoepitopes from sequence alone and provide guidance for developing novel, neoepitope-based personalized therapies.

Structure deposition and release

Deposited: 2019-10-04
Released: 2020-08-19
Revised: 2020-10-28

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: KQWLVWLFL

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 LYS

TYR159
TYR59
THR163
CYS164
TYR171
LYS66
GLU63
TYR7
MET5
TRP167
P2 GLN

VAL67
TYR159
TYR9
LYS66
TYR7
HIS70
TYR99
GLU63
MET45
P3 TRP

HIS70
TYR99
LYS66
HIS114
VAL152
LEU156
GLN155
ARG97
TYR159
P4 LEU

HIS70
LYS66
P5 VAL

GLN155
HIS70
P6 TRP

GLN72
ALA69
THR73
P7 LEU

ARG97
TYR116
THR73
TRP147
VAL152
ASP77
HIS114
P8 PHE

THR73
TRP147
ASP77
THR143
LYS146
GLN72
VAL76
P9 LEU

LYS146
TYR116
THR80
LEU81
VAL95
ASP77
ILE124
TRP147
TYR123
TYR84
THR143

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
GLY63
ARG66
ARG7
B Pocket

ILE24
PHE34
ARG45
GLY63
ARG66
LYS67
ARG7
ALA70
PHE9
MET99
C Pocket

ALA70
GLN73
THR74
PHE9
GLN97
D Pocket

TYR114
GLU155
GLN156
ALA159
TYR160
MET99
E Pocket

TYR114
LYS147
HIS152
GLN156
GLN97
F Pocket

GLN116
ASP123
THR143
HIS146
LYS147
VAL77
GLY80
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
MIQRTPKIQVYSRHPAENGKSNFLNCYVSGFHPSDIEVDLLKNGERIEKVEHSDLSFSKD
        70        80        90
WSFYLLYYTEFTPTEKDEYACRVNHVTLSQPKIVKWDRDM

2. Class I alpha
HLA-A*02:06
IPD-IMGT/HLA
[ipd-imgt:HLA28627]
        10        20        30        40        50        60
MGSHSMRYFYTSVSRPGRGEPRFIAVGYVDDTQFVRFDSDAASQRMEPRAPWIEQEGPEY
        70        80        90       100       110       120
WDGETRKVKAHSQTHRVDLGTLRGYYNQSEAGSHTVQRMYGCDVGSDWRFLRGYHQYAYD
       130       140       150       160       170       180
GKDYIALKEDLRSWTAADMAAQTTKHKWEAAHVAEQLRAYLEGTCVEWLRRYLENGKETL
       190       200       210       220       230       240
QRTDAPKTHMTHHAVSDHEATLRCWALSFYPAEITLTWQRDGEDQTQDTELVETRPAGDG
       250       260       270
TFQKWAAVVVPSGQEQRYTCHVQHEGLPKPLTLRWE

3. Peptide
KQWLVWLFL

4. T cell receptor alpha
T cell receptor alpha
TRAV38
        10        20        30        40        50        60
MAQTVTQSQPEMSVQEAETVTLSCTYDTSESDYYLFWYKQPPSRQMILVIRQEAYKQQNA
        70        80        90       100       110       120
TENRFSVNFQKAAKSFSLKISDSQLGDAAMYFCAFMDSNYQLIWGAGTKLIIKPNIQNPD
       130       140       150       160       170       180
PAVYQLRDSKSSDKSVCLFTDFDSQTNVSQSKDSDVYITDKCVLDMRSMDFKSNSAVAWS
       190       200
NKSDFACANAFNNSIIPEDTFFPSPESS

5. T cell receptor beta
T cell receptor beta
TRBV12
        10        20        30        40        50        60
MDAGVIQSPRHEVTEMGQEVTLRCKPISGHNSLFWYRQTMMRGLELLIYFNNNVPIDDSG
        70        80        90       100       110       120
MPEDRFSAKMPNASFSTLKIQPSEPRDSAVYFCASSRTSPTDTQYFGPGTRLTVLEDLKN
       130       140       150       160       170       180
VFPPEVAVFEPSEAEISHTQKATLVCLATGFYPDHVELSWWVNGKEVHSGVCTDPQPLKE
       190       200       210       220       230       240
QPALNDSRYALSSRLRVSATFWQDPRNHFRCQVQFYGLSENDEWTQDRAKPVTQIVSAEA

WGRAD


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. 6UK4 assembly 1  

Components

MHC Class I alpha chain [cif]
  1. 6UK4 assembly 1  
MHC Class I antigen binding domain (alpha1/alpha2) [cif]
  1. 6UK4 assembly 1  
Peptide only [cif]
  1. 6UK4 assembly 1  

Derived data

Data for this page [json]
https://api.histo.fyi/v1/structures/6uk4

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