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6NCA

HLA-A*02:01 binding "YVLDHLIVV" at 3.30Å 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
['a', 'b', 'c', 'd', 'f', 'g', 'h', 's', 'j', 'k', 'l', 'm', 'n', 'o', 'p', 'q', 'r', 'i', 't', 'e']
2. Class I alpha
HLA-A*02:01
['A', 'B', 'C', 'D', 'E', 'F', 'G', 'H', 'S', 'J', 'K', 'L', 'M', 'N', 'O', 'P', 'Q', 'R', 'I', 'T']
3. Peptide
YVLDHLIVV
['Y', 'u', 'z', 'y', '8', 'w', '4', '3', 'W', '6', 'x', '5', 'X', 'v', '2', 'U', 'Z', 'V', '7', '1']

Species

Locus / Allele group

HLA-A / HLA-A*02

Publication

CDR3����drives selection of the immunodominant Epstein Barr virus (EBV) BRLF1-specific CD8 T cell receptor repertoire in primary infection.

Kamga L, Gil A, Song I, Brody R, Ghersi D, Aslan N, Stern LJ, Selin LK, Luzuriaga K
PLoS Pathog. (2019) 15, e1008122 [doi:10.1371/journal.ppat.1008122]  [pubmed:31765434] 

The T cell receptor (TCR) repertoire is an essential component of the CD8 T-cell immune response. Here, we seek to investigate factors that drive selection of TCR repertoires specific to the HLA-A2-restricted immunodominant epitope BRLF1109-117 (YVLDHLIVV) over the course of primary Epstein Barr virus (EBV) infection. Using single-cell paired TCRαβ sequencing of tetramer sorted CD8 T cells ex vivo, we show at the clonal level that recognition of the HLA-A2-restricted BRLF1 (YVL-BR, BRLF-1109) epitope is mainly driven by the TCRα chain. For the first time, we identify a CDR3α (complementarity determining region 3 α) motif, KDTDKL, resulting from an obligate AV8.1-AJ34 pairing that was shared by all four individuals studied. This observation coupled with the fact that this public AV8.1-KDTDKL-AJ34 TCR pairs with multiple different TCRβ chains within the same donor (median 4; range: 1-9), suggests that there are some unique structural features of the interaction between the YVL-BR/MHC and the AV8.1-KDTDKL-AJ34 TCR that leads to this high level of selection. Newly developed TCR motif algorithms identified a lysine at position 1 of the CDR3α motif that is highly conserved and likely important for antigen recognition. Crystal structure analysis of the YVL-BR/HLA-A2 complex revealed that the MHC-bound peptide bulges at position 4, exposing a negatively charged aspartic acid that may interact with the positively charged lysine of CDR3α. TCR cloning and site-directed mutagenesis of the CDR3α lysine ablated YVL-BR-tetramer staining and substantially reduced CD69 upregulation on TCR mutant-transduced cells following antigen-specific stimulation. Reduced activation of T cells expressing this CDR3 motif was also observed following exposure to mutated (D4A) peptide. In summary, we show that a highly public TCR repertoire to an immunodominant epitope of a common human virus is almost completely selected on the basis of CDR3α and provide a likely structural basis for the selection. These studies emphasize the importance of examining TCRα, as well as TCRβ, in understanding the CD8 T cell receptor repertoire.

Structure deposition and release

Deposited: 2018-12-11
Released: 2019-10-23
Revised: 2020-01-29

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: YVLDHLIVV

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 TYR

TYR59
GLU63
TRP167
MET5
TYR171
TYR159
THR163
LYS66
TYR7
 P2 VAL

VAL67
TYR159
LYS66
MET45
TYR7
PHE9
TYR99
GLU63
HIS70
 P3 LEU

ARG97
LEU156
TYR99
TYR159
HIS70
LYS66
HIS114
 P4 ASP

LYS66
THR163
HIS70
 P5 HIS

VAL152
GLN155
HIS70
 P6 LEU

HIS70
LYS66
THR73
ALA69
 P7 ILE

THR73
TRP147
HIS114
VAL152
ASP77
LEU156
ARG97
 P8 VAL

THR80
TRP147
ASP77
THR73
THR143
VAL76
 P9 VAL

THR80
ASP77
TYR84
TYR123
LYS146
TRP147
THR143
TYR116
LEU81

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

TYR159
THR163
TRP167
TYR171
MET5
TYR59
GLU63
LYS66
TYR7
B Pocket

ALA24
VAL34
MET45
GLU63
LYS66
VAL67
TYR7
HIS70
PHE9
TYR99
C Pocket

HIS70
THR73
HIS74
PHE9
ARG97
D Pocket

HIS114
GLN155
LEU156
TYR159
LEU160
TYR99
E Pocket

HIS114
TRP147
VAL152
LEU156
ARG97
F Pocket

TYR116
TYR123
THR143
LYS146
TRP147
ASP77
THR80
LEU81
TYR84
VAL95

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*02:01
IPD-IMGT/HLA
[ipd-imgt:HLA35266]
        10        20        30        40        50        60
GSHSMRYFFTSVSRPGRGEPRFIAVGYVDDTQFVRFDSDAASQRMEPRAPWIEQEGPEYW
        70        80        90       100       110       120
DGETRKVKAHSQTHRVDLGTLRGYYNQSEAGSHTVQRMYGCDVGSDWRFLRGYHQYAYDG
       130       140       150       160       170       180
KDYIALKEDLRSWTAADMAAQTTKHKWEAAHVAEQLRAYLEGTCVEWLRRYLENGKETLQ
       190       200       210       220       230       240
RTDAPKTHMTHHAVSDHEATLRCWALSFYPAEITLTWQRDGEDQTQDTELVETRPAGDGT
       250       260       270
FQKWAAVVVPSGQEQRYTCHVQHEGLPKPLTLRWE
3. Peptide
YVLDHLIVV

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

Data can be downloaded to your local machine from the links below.
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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. 6NCA assembly 1  
  2. 6NCA assembly 10  
  3. 6NCA assembly 11  
  4. 6NCA assembly 12  
  5. 6NCA assembly 13  
  6. 6NCA assembly 14  
  7. 6NCA assembly 15  
  8. 6NCA assembly 16  
  9. 6NCA assembly 17  
  10. 6NCA assembly 18  
  11. 6NCA assembly 19  
  12. 6NCA assembly 2  
  13. 6NCA assembly 20  
  14. 6NCA assembly 3  
  15. 6NCA assembly 4  
  16. 6NCA assembly 5  
  17. 6NCA assembly 6  
  18. 6NCA assembly 7  
  19. 6NCA assembly 8  
  20. 6NCA assembly 9  

Components

MHC Class I alpha chain [cif]
  1. 6NCA assembly 1  
  2. 6NCA assembly 10  
  3. 6NCA assembly 11  
  4. 6NCA assembly 12  
  5. 6NCA assembly 13  
  6. 6NCA assembly 14  
  7. 6NCA assembly 15  
  8. 6NCA assembly 16  
  9. 6NCA assembly 17  
  10. 6NCA assembly 18  
  11. 6NCA assembly 19  
  12. 6NCA assembly 2  
  13. 6NCA assembly 20  
  14. 6NCA assembly 3  
  15. 6NCA assembly 4  
  16. 6NCA assembly 5  
  17. 6NCA assembly 6  
  18. 6NCA assembly 7  
  19. 6NCA assembly 8  
  20. 6NCA assembly 9  
MHC Class I antigen binding domain (alpha1/alpha2) [cif]
  1. 6NCA assembly 1  
  2. 6NCA assembly 10  
  3. 6NCA assembly 11  
  4. 6NCA assembly 12  
  5. 6NCA assembly 13  
  6. 6NCA assembly 14  
  7. 6NCA assembly 15  
  8. 6NCA assembly 16  
  9. 6NCA assembly 17  
  10. 6NCA assembly 18  
  11. 6NCA assembly 19  
  12. 6NCA assembly 2  
  13. 6NCA assembly 20  
  14. 6NCA assembly 3  
  15. 6NCA assembly 4  
  16. 6NCA assembly 5  
  17. 6NCA assembly 6  
  18. 6NCA assembly 7  
  19. 6NCA assembly 8  
  20. 6NCA assembly 9  
Peptide only [cif]
  1. 6NCA assembly 1  
  2. 6NCA assembly 10  
  3. 6NCA assembly 11  
  4. 6NCA assembly 12  
  5. 6NCA assembly 13  
  6. 6NCA assembly 14  
  7. 6NCA assembly 15  
  8. 6NCA assembly 16  
  9. 6NCA assembly 17  
  10. 6NCA assembly 18  
  11. 6NCA assembly 19  
  12. 6NCA assembly 2  
  13. 6NCA assembly 20  
  14. 6NCA assembly 3  
  15. 6NCA assembly 4  
  16. 6NCA assembly 5  
  17. 6NCA assembly 6  
  18. 6NCA assembly 7  
  19. 6NCA assembly 8  
  20. 6NCA assembly 9  

Derived data

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

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


Creative Commons Licence
This work is licensed under a Creative Commons Attribution 4.0 International License.