HLA-A*02:01 presenting "SLLMWITQV" to Alpha/Beta T cell receptor at 1.70Å resolution
Data provenance
Information sections
- Publication
- Peptide details
- Peptide neighbours
- Binding cleft pockets
- Chain sequences
- Downloadable data
- Data license
- Footnotes
Complex type
Class i with peptide and alpha beta tcr
HLA-A*02:01
SLLMWITQV
TRAV21
TRBV6
Species
Locus / Allele group
Structural and kinetic basis for heightened immunogenicity of T cell vaccines.
Analogue peptides with enhanced binding affinity to major histocompatibility class (MHC) I molecules are currently being used in cancer patients to elicit stronger T cell responses. However, it remains unclear as to how alterations of anchor residues may affect T cell receptor (TCR) recognition. We correlate functional, thermodynamic, and structural parameters of TCR-peptide-MHC binding and demonstrate the effect of anchor residue modifications of the human histocompatibility leukocyte antigens (HLA)-A2 tumor epitope NY-ESO-1(157-165)-SLLMWITQC on TCR recognition. The crystal structure of the wild-type peptide complexed with a specific TCR shows that TCR binding centers on two prominent, sequential, peptide sidechains, methionine-tryptophan. Cysteine-to-valine substitution at peptide position 9, while optimizing peptide binding to the MHC, repositions the peptide main chain and generates subtly enhanced interactions between the analogue peptide and the TCR. Binding analyses confirm tighter binding of the analogue peptide to HLA-A2 and improved soluble TCR binding. Recognition of analogue peptide stimulates faster polarization of lytic granules to the immunological synapse, reduces dependence on CD8 binding, and induces greater numbers of cross-reactive cytotoxic T lymphocyte to SLLMWITQC. These results provide important insights into heightened immunogenicity of analogue peptides and highlight the importance of incorporating structural data into the process of rational optimization of superagonist peptides for clinical trials.
Structure deposition and release
Data provenance
Publication data retrieved from PDBe REST API8 and PMCe REST API9
Other structures from this publication
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
TYR171
THR163
TYR159
TYR59
LYS66
GLU63
MET5
TYR7
TRP167
PHE33
|
P2
LEU
HIS70
TYR7
VAL67
PHE9
TYR99
TYR159
LYS66
MET45
GLU63
|
P3
LEU
HIS70
TYR99
TYR159
LYS66
HIS114
LEU156
|
P4
MET
LYS66
HIS70
|
P6
ILE
ALA69
HIS70
THR73
LYS66
ARG97
|
P7
THR
ARG97
THR73
VAL152
ASP77
TRP147
|
P8
GLN
THR73
VAL76
ASP77
LYS146
TRP147
|
P9
VAL
TYR123
TYR84
THR143
THR80
TYR116
LEU81
ASP77
LYS146
TRP147
THR142
|
Colour key
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]
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
Data provenance
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 FQKWAAVVVPSGQEQRYTCHVQHEGLPKPLTLRWEP |
3. Peptide
|
SLLMWITQV
|
4. T cell receptor alpha
T cell receptor alpha
TRAV21
|
10 20 30 40 50 60
QEVTQIPAALSVPEGENLVLNCSFTDSAIYNLQWFRQDPGKGLTSLLLIQSSQREQTSGR 70 80 90 100 110 120 LNASLDKSSGRSTLYIAASQPGDSATYLCAVRPTSGGSYIPTFGRGTSLIVHPYIQNPDP 130 140 150 160 170 180 AVYQLRDSKSSDKSVCLFTDFDSQTNVSQSKDSDVYITDKCVLDMRSMDFKSNSAVAWSN 190 200 KSDFACANAFNNSIIPEDTFFPS |
5. T cell receptor beta
T cell receptor beta
TRBV6
|
10 20 30 40 50 60
GVTQTPKFQVLKTGQSMTLQCAQDMNHEYMSWYRQDPGMGLRLIHYSVGAGITDQGEVPN 70 80 90 100 110 120 GYNVSRSTTEDFPLRLLSAAPSQTSVYFCASSYVGNTGELFFGEGSRLTVLEDLKNVFPP 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
Components
Data license
Footnotes
- Protein Data Bank Europe - Coordinate Server
- 1HHK - HLA-A*02:01 binding LLFGYPVYV at 2.5Å resolution - PDB entry for 1HHK
- Protein structure alignment by incremental combinatorial extension (CE) of the optimal path. - PyMol CEALIGN Method - Publication
- PyMol - PyMol.org/pymol
- Levenshtein distance - Wikipedia entry
- Protein Data Bank Europe REST API - Molecules endpoint
- 3Dmol.js: molecular visualization with WebGL - 3DMol.js - Publication
- Protein Data Bank Europe REST API - Publication endpoint
- PubMed Central Europe REST API - Articles endpoint
This work is licensed under a Creative Commons Attribution 4.0 International License.