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6D78

HLA-A*02:01 presenting "AAGIGILTV" to Alpha/Beta T cell receptor at 2.35Å 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*02:01
['A']
3. Peptide
AAGIGILTV
['C']
4. T cell receptor alpha
TRAV12
['D']
5. T cell receptor beta
TRBV6
['E']

Species


Locus / Allele group


Publication

Improving T Cell Receptor On-Target Specificity via Structure-Guided Design.

Hellman LM, Foley KC, Singh NK, Alonso JA, Riley TP, Devlin JR, Ayres CM, Keller GLJ, Zhang Y, Vander Kooi CW, Nishimura MI, Baker BM
Mol. Ther. (2019) 27, 300-313 [doi:10.1016/j.ymthe.2018.12.010]  [pubmed:30617019

T cell receptors (TCRs) have emerged as a new class of immunological therapeutics. However, though antigen specificity is a hallmark of adaptive immunity, TCRs themselves do not possess the high specificity of monoclonal antibodies. Although a necessary function of T cell biology, the resulting cross-reactivity presents a significant challenge for TCR-based therapeutic development, as it creates the potential for off-target recognition and immune toxicity. Efforts to enhance TCR specificity by mimicking the antibody maturation process and enhancing affinity can inadvertently exacerbate TCR cross-reactivity. Here we demonstrate this concern by showing that even peptide-targeted mutations in the TCR can introduce new reactivities against peptides that bear similarity to the original target. To counteract this, we explored a novel structure-guided approach for enhancing TCR specificity independent of affinity. Tested with the MART-1-specific TCR DMF5, our approach had a small but discernible impact on cross-reactivity toward MART-1 homologs yet was able to eliminate DMF5 cross-recognition of more divergent, unrelated epitopes. Our study provides a proof of principle for the use of advanced structure-guided design techniques for improving TCR specificity, and it suggests new ways forward for enhancing TCRs for therapeutic use.

Structure deposition and release

Deposited: 2018-04-24
Released: 2019-04-03
Revised: 2020-01-01

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: AAGIGILTV

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

P10 VAL

THR80
TYR84
LEU81
TRP147
THR143
LYS146
TYR116
TYR123
ASP77
P2 ALA

TYR159
TYR7
LYS66
HIS70
PHE9
TYR99
GLU63
P3 ALA

TYR159
LYS66
TYR99
HIS70
P4 GLY

TYR159
LYS66
P5 ILE

LEU156
GLN155
TYR159
ALA158
P6 GLY

ARG97
VAL152
HIS114
LEU156
GLN155
P7 ILE

THR73
VAL152
TYR99
HIS70
HIS114
LEU156
GLN155
ARG97
P8 LEU

THR73
ASP77
VAL152
TRP147
LYS146
ARG97
ALA150
P9 THR

THR73
TRP147
ASP77
THR143
LYS146
VAL76

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*02:01
IPD-IMGT/HLA
[ipd-imgt:HLA35266]
        10        20        30        40        50        60
MGSHSMRYFFTSVSRPGRGEPRFIAVGYVDDTQFVRFDSDAASQRMEPRAPWIEQEGPEY
        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
AAGIGILTV

4. T cell receptor alpha
T cell receptor alpha
TRAV12
        10        20        30        40        50        60
MKEVEQNSGPLSVPEGAIASLNCTYSYRGSQSFFWYRQYSGKSPELIMFIYSNGDKEDGR
        70        80        90       100       110       120
FTAQLNKASQYVSLLIRDSQPSDSATYLCAVNFGGGKLIFGQGTELSVKPNIQNPDPAVY
       130       140       150       160       170       180
QLRDSKSSDKSVCLFTDFDSQTNVSQSKDSDVYITDKCVLDMRSMDFKSNSAVAWSNKSD
       190
FACANAFNNSIIPEDTFFPS

5. T cell receptor beta
T cell receptor beta
TRBV6
        10        20        30        40        50        60
MIAGITQAPTSQILAAGRRMTLRCTQDMRHNAMYWYRQDLGLGLRLIHYSNTAGTTGKGE
        70        80        90       100       110       120
VPDGYSVSRANTDDFPLTLASAVPSQTSVYFCASSWSFGTEAFFGQGTRLTVVEDLNKVF
       130       140       150       160       170       180
PPEVAVFEPSEAEISHTQKATLVCLATGFYPDHVELSWWVNGKEVHSGVCTDPQPLKEQP
       190       200       210       220       230       240
ALNDSRYALSSRLRVSATFWQDPRNHFRCQVQFYGLSENDEWTQDRAKPVTQIVSAEAWG

RAD


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. 6D78 assembly 1  

Components

MHC Class I alpha chain [cif]
  1. 6D78 assembly 1  
MHC Class I antigen binding domain (alpha1/alpha2) [cif]
  1. 6D78 assembly 1  
Peptide only [cif]
  1. 6D78 assembly 1  

Derived data

Data for this page [json]
https://api.histo.fyi/v1/structures/6d78

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