6UJ9

HLA-B*07:02 binding "SPNGTIQNIL" with antibody at 2.90Å 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.

Complex type

Class i with peptide and antibody

1. ab_heavy

['H']

2. ab_light

['L']

3. Beta 2 microglobulin

['B']

4. Class I alpha
HLA-B*07:02

['A']

5. Peptide
SPNGTIQNIL

['C']

Species

Homo sapiens (Human)

Locus / Allele group

HLA-B / HLA-B*07

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 IDH2^R140Q-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: SPNGTIQNIL

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

TYR59

TYR7

ARG62

ASN63

TRP167

MET5

TYR171

PHE33

TYR159

P10 LEU

LEU81

ASN80

SER77

TYR84

THR143

TYR116

TYR123

LEU95

LYS146

TRP147

ILE124

P2 PRO

TYR67

ARG62

TYR159

TYR7

TYR9

ILE66

TYR99

ASN63

P3 ASN

ARG156

ILE66

TYR99

GLN155

TYR159

TYR9

P4 GLY

ILE66

TYR159

ARG62

P5 THR

GLN155

P6 ILE

GLN155

THR73

GLU152

ALA69

P7 GLN

TRP147

THR73

TYR9

SER97

GLU152

GLN70

ASP114

ARG156

TYR116

GLN155

P8 ASN

ALA150

GLU152

ARG156

LYS146

TRP147

THR73

P9 ILE

GLU76

TRP147

THR73

ASN80

SER77

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. ab_heavy ab_heavy	10 20 30 40 50 60 EVQLVESGGGLVQPGGSLRLSCAASGFNVKYYMMHWVRQAPGKGLEWVAAISPGYDYTYY 70 80 90 100 110 120 ADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRSYWRYSVDVWGQGTLVTVSSAS 130 140 150 160 170 180 TKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGL 190 200 210 YSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEP

2. ab_light ab_light	10 20 30 40 50 60 DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPS 70 80 90 100 110 120 RFSGSRSGTDFTLTISSLQPEDFATYYCQQVYSSPFTFGQGTKVEIKRTVAAPSVFIFPP 130 140 150 160 170 180 SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT 190 200 210 LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

3. Beta 2 microglobulin Beta 2 microglobulin	10 20 30 40 50 60 MSRSVALAVLALLSLSGLEAIQRTPKIQVYSRHPAENGKSNFLNCYVSGFHPSDIEVDLL 70 80 90 100 110 KNGERIEKVEHSDLSFSKDWSFYLLYYTEFTPTEKDEYACRVNHVTLSQPKIVKWDRDM

4. Class I alpha HLA-B07:02 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

5. Peptide	SPNGTIQNIL

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]

6UJ9 assembly 1

Components

MHC Class I alpha chain [cif]

6UJ9 assembly 1

MHC Class I antigen binding domain (alpha1/alpha2) [cif]

6UJ9 assembly 1

Peptide only [cif]

6UJ9 assembly 1

Derived data

Data for this page [json]

https://api.histo.fyi/v1/structures/6uj9

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

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.