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6UJ8

HLA-B*07:02 binding "SPNGTIRNIL" at 2.25Å 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
['B', 'E']
2. Class I alpha
HLA-B*07:02
['A', 'D']
3. Peptide
SPNGTIRNIL
['C', 'F']

Species


Locus / Allele group


Publication

Structural engineering of chimeric antigen receptors targeting HLA-restricted neoantigens.

Hwang MS, Miller MS, Thirawatananond P, Douglass J, Wright KM, Hsiue EH, Mog BJ, Aytenfisu TY, Murphy MB, Aitana Azurmendi P, Skora AD, Pearlman AH, Paul S, DiNapoli SR, Konig MF, Bettegowda C, Pardoll DM, Papadopoulos N, Kinzler KW, Vogelstein B, Zhou S, Gabelli SB
Nat Commun (2021) 12, 5271 [doi:10.1038/s41467-021-25605-4]  [pubmed:34489470

Chimeric antigen receptor (CAR) T cells have emerged as a promising class of therapeutic agents, generating remarkable responses in the clinic for a subset of human cancers. One major challenge precluding the wider implementation of CAR therapy is the paucity of tumor-specific antigens. Here, we describe the development of a CAR targeting the tumor-specific isocitrate dehydrogenase 2 (IDH2) with R140Q mutation presented on the cell surface in complex with a common human leukocyte antigen allele, HLA-B*07:02. Engineering of the hinge domain of the CAR, as well as crystal structure-guided optimization of the IDH2R140Q-HLA-B*07:02-targeting moiety, enhances the sensitivity and specificity of CARs to enable targeting of this HLA-restricted neoantigen. This approach thus holds promise for the development and optimization of immunotherapies specific to other cancer driver mutations that are difficult to target by conventional means.

Structure deposition and release

Deposited: 2019-10-02
Released: 2021-05-05
Revised: 2021-11-17

Data provenance

Publication data retrieved from PDBe REST API8 and PMCe REST API9

Other structures from this publication


Peptide details

Length: Decamer (10 amino acids)

Sequence: SPNGTIRNIL

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 SER

PHE33
TRP167
MET5
TYR159
TYR59
ASN63
TYR7
TYR171
P10 LEU

SER77
TYR84
THR143
LEU95
ASN80
LYS146
TRP147
TYR123
TYR116
LEU81
P2 PRO

TYR7
GLU163
ASN63
GLU45
TYR99
TYR159
TYR9
ILE66
TYR67
P3 ASN

GLN155
TYR159
ARG156
TYR9
ILE66
TYR99
P4 GLY

GLU163
TYR159
ARG62
ILE66
P5 THR

GLN155
P6 ILE

THR73
ALA69
GLU152
GLN155
P7 ARG

GLN70
ARG156
TYR116
GLU152
GLN155
THR73
TYR99
TYR9
SER97
ASP114
P8 ASN

THR73
SER77
GLU152
GLN155
TRP147
ARG156
ALA150
TYR116
P9 ILE

TRP147
THR73
SER77
GLU76
THR143
ASN80
LYS146

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
ARG63
GLN66
ARG7
B Pocket

ILE24
PHE34
ARG45
ARG63
GLN66
ILE67
ARG7
ALA70
PHE9
MET99
C Pocket

ALA70
GLN73
THR74
PHE9
GLN97
D Pocket

HIS114
GLU155
GLN156
ALA159
TYR160
MET99
E Pocket

HIS114
LYS147
ARG152
GLN156
GLN97
F Pocket

GLN116
ASP123
ILE143
ARG146
LYS147
GLU77
ARG80
ASN81
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
MSRSVALAVLALLSLSGLEAIQRTPKIQVYSRHPAENGKSNFLNCYVSGFHPSDIEVDLL
        70        80        90       100       110
KNGERIEKVEHSDLSFSKDWSFYLLYYTEFTPTEKDEYACRVNHVTLSQPKIVKWDRDM

2. Class I alpha
HLA-B*07:02
IPD-IMGT/HLA
[ipd-imgt:HLA34746]
        10        20        30        40        50        60
MGSHSMRYFYTSVSRPGRGEPRFISVGYVDDTQFVRFDSDAASPREEPRAPWIEQEGPEY
        70        80        90       100       110       120
WDRNTQIYKAQAQTDRESLRNLRGYYNQSEAGSHTLQSMYGCDVGPDGRLLRGHDQYAYD
       130       140       150       160       170       180
GKDYIALNEDLRSWTAADTAAQITQRKWEAAREAEQRRAYLEGECVEWLRRYLENGKDKL
       190       200       210       220       230       240
ERADPPKTHVTHHPISDHEATLRCWALGFYPAEITLTWQRDGEDQTQDTELVETRPAGDR
       250       260       270       280       290
TFQKWAAVVVPSGEEQRYTCHVQHEGLPKPLTLRWEPSSQSGSLHHILDAQKMVWNHR

3. Peptide
SPNGTIRNIL


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. 6UJ8 assembly 1  
  2. 6UJ8 assembly 2  

Components

MHC Class I alpha chain [cif]
  1. 6UJ8 assembly 1  
  2. 6UJ8 assembly 2  
MHC Class I antigen binding domain (alpha1/alpha2) [cif]
  1. 6UJ8 assembly 1  
  2. 6UJ8 assembly 2  
Peptide only [cif]
  1. 6UJ8 assembly 1  
  2. 6UJ8 assembly 2  

Derived data

Data for this page [json]
https://api.histo.fyi/v1/structures/6uj8

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