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5BS0

HLA-A*01:01 presenting "ESDPIVAQY" to Alpha/Beta T cell receptor at 2.40Å 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*01:01
['A']
3. Peptide
ESDPIVAQY
['C']
4. T cell receptor alpha
TRAV21
['D']
5. T cell receptor beta
TRBV5
['E']

Species


Locus / Allele group


Publication

Direct molecular mimicry enables off-target cardiovascular toxicity by an enhanced affinity TCR designed for cancer immunotherapy.

Raman MC, Rizkallah PJ, Simmons R, Donnellan Z, Dukes J, Bossi G, Le Provost GS, Todorov P, Baston E, Hickman E, Mahon T, Hassan N, Vuidepot A, Sami M, Cole DK, Jakobsen BK
Sci Rep (2016) 6, 18851 [doi:10.1038/srep18851]  [pubmed:26758806

Natural T-cell responses generally lack the potency to eradicate cancer. Enhanced affinity T-cell receptors (TCRs) provide an ideal approach to target cancer cells, with emerging clinical data showing significant promise. Nevertheless, the risk of off target reactivity remains a key concern, as exemplified in a recent clinical report describing fatal cardiac toxicity, following administration of MAGE-A3 specific TCR-engineered T-cells, mediated through cross-reactivity with an unrelated epitope from the Titin protein presented on cardiac tissue. Here, we investigated the structural mechanism enabling TCR cross-recognition of MAGE-A3 and Titin, and applied the resulting data to rationally design mutants with improved antigen discrimination, providing a proof-of-concept strategy for altering the fine specificity of a TCR towards an intended target antigen. This study represents the first example of direct molecular mimicry leading to clinically relevant fatal toxicity, mediated by a modified enhanced affinity TCR designed for cancer immunotherapy. Furthermore, these data demonstrate that self-antigens that are expressed at high levels on healthy tissue should be treated with extreme caution when designing immuno-therapeutics.

Structure deposition and release

Deposited: 2015-06-01
Released: 2016-03-02
Revised: 2016-03-02

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: ESDPIVAQY

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 GLU

MET5
TYR171
TYR159
GLN62
TYR7
GLY167
TYR59
ARG163
GLU63
ARG170
CYS164
P2 SER

MET45
MET67
ASN66
TYR99
TYR7
TYR159
ARG163
GLU63
P3 ASP

ARG163
ASN66
TYR99
ARG156
GLN155
TYR159
P4 PRO

ASN66
TYR159
ARG163
P5 ILE

ARG156
GLN155
P6 VAL

ALA69
THR73
HIS70
P7 ALA

ARG156
ARG114
THR73
ASN77
TRP147
P8 GLN

THR143
THR73
ASN77
LYS146
TRP147
P9 TYR

LYS146
TRP147
ASP116
ILE142
LEU81
ILE97
THR80
ARG114
THR143
TYR84
TYR123
ILE95
ASN77
ILE124

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
ARG163
GLY167
TYR171
MET5
TYR59
GLU63
ASN66
TYR7
B Pocket

ALA24
VAL34
MET45
GLU63
ASN66
MET67
TYR7
HIS70
PHE9
TYR99
C Pocket

HIS70
THR73
ASP74
PHE9
ILE97
D Pocket

ARG114
GLN155
ARG156
TYR159
LEU160
TYR99
E Pocket

ARG114
TRP147
ALA152
ARG156
ILE97
F Pocket

ASP116
TYR123
THR143
LYS146
TRP147
ASN77
THR80
LEU81
TYR84
ILE95

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*01:01
IPD-IMGT/HLA
[ipd-imgt:HLA34767]
        10        20        30        40        50        60
GSHSMRYFFTSVSRPGRGEPRFIAVGYVDDTQFVRFDSDAASQKMEPRAPWIEQEGPEYW
        70        80        90       100       110       120
DQETRNMKAHSQTDRANLGTLRGYYNQSEDGSHTIQIMYGCDVGPDGRFLRGYRQDAYDG
       130       140       150       160       170       180
KDYIALNEDLRSWTAADMAAQITKRKWEAVHAAEQRRVYLEGRCVDGLRRYLENGKETLQ
       190       200       210       220       230       240
RTDPPKTHMTHHPISDHEATLRCWALGFYPAEITLTWQRDGEDQTQDTELVETRPAGDGT
       250       260       270
FQKWAAVVVPSGEEQRYTCHVQHEGLPKPLTLRWP

3. Peptide
ESDPIVAQY

4. T cell receptor alpha
T cell receptor alpha
TRAV21
        10        20        30        40        50        60
AQEVTQIPAALSVPEGENLVLNCSFTDSAIYNLQWFRQDPGKGLTSLLYVRPYQREQTSG
        70        80        90       100       110       120
RLNASLDKSSGRSTLYIAASQPGDSATYLCAVRPGGAGPFFVVFGKGTKLSVIPNIQNPD
       130       140       150       160       170       180
PAVYQLRDSKSSDKSVCLFTDFDSQTNVSQSKDSDVYITDKCVLDMRSMDFKSNSAVAWS
       190
NKSDFACANAFNNSIIP

5. T cell receptor beta
T cell receptor beta
TRBV5
        10        20        30        40        50        60
AGVTQTPRYLIKTRGQQVTLSCSPISGHRSVSWYQQTPGQGLQFLFEYFSETQRNKGNFP
        70        80        90       100       110       120
GRFSGRQFSNSRSEMNVSTLELGDSALYLCASSFNMATGQYFGPGTRLTVTEDLKNVFPP
       130       140       150       160       170       180
EVAVFEPSEAEISHTQKATLVCLATGFYPDHVELSWWVNGKEVHSGVCTDPQPLKEQPAL
       190       200       210       220       230       240
NDSRYALSSRLRVSATFWQDPRNHFRCQVQFYGLSENDEWTQDRAKPVTQIVSAEAWGRA

D


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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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. 5BS0 assembly 1  

Components

MHC Class I alpha chain [cif]
  1. 5BS0 assembly 1  
MHC Class I antigen binding domain (alpha1/alpha2) [cif]
  1. 5BS0 assembly 1  
Peptide only [cif]
  1. 5BS0 assembly 1  

Derived data

Data for this page [json]
https://api.histo.fyi/v1/structures/5bs0

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