Alpha This is a work in progress and may change. Your feedback is very welcome.
  


6O9B

HLA-A*03:01 binding "TTAPSLSGK" at 2.20Å 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']
2. Class I alpha
HLA-A*03:01
['A']
3. Peptide
TTAPSLSGK
['C']

Species


Locus / Allele group


Publication

An engineered antibody fragment targeting mutant ��-catenin via Major Histocompatibility Complex I neoantigen presentation.

Miller MS, Douglass J, Hwang MS, Skora AD, Murphy M, Papadopoulos N, Kinzler KW, Vogelstein B, Zhou S, Gabelli SB
J. Biol. Chem. (2019) [doi:10.1074/jbc.RA119.010251]  [pubmed:31690625

Mutations in CTNNB1, the gene encoding β-catenin, are common in colon and liver cancers, the most frequent mutation affecting Ser-45 in β-catenin. Peptides derived from WT β-catenin have previously been shown to be presented on the cell surface as part of major histocompatibility complex (MHC) class I, suggesting an opportunity for targeting this common driver gene mutation with antibody-based therapies. Here, crystal structures of both the WT and S45F mutant peptide bound to HLA-A*03:01 at 2.20 and 2.45 Å resolutions, respectively, confirmed the accessibility of the phenylalanine residue for antibody recognition. Phage display was then used to identify single-chain variable fragment clones that selectively bind the S45F mutant peptide presented in HLA-A*03:01 and have minimal WT or other off-target binding. Following the initial characterization of five clones, we selected a single clone, E10, for further investigation. We developed a computational model of the binding of E10 to the mutant peptide-bound HLA-A3, incorporating data from affinity maturation as initial validation. In the future, our model may be used to design clones with maintained specificity and higher affinity. Such derivatives could be adapted into either cell-based (CAR-T) or protein-based (bispecific T-cell engagers) therapies to target cancer cells harboring the S45F mutation in CTNNB1.

Structure deposition and release

Deposited: 2019-03-13
Released: 2019-11-13
Revised: 2019-12-25

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: TTAPSLSGK

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 THR

TYR159
TRP167
MET5
TYR59
TYR171
THR163
GLU63
TYR7
P2 THR

TYR99
GLU63
TYR159
VAL67
TYR7
PHE9
ASN66
MET45
P3 ALA

LEU156
ASN66
TYR99
TYR159
P4 PRO

GLN155
TYR159
ASN66
P5 SER

ALA69
GLN155
GLN70
THR73
ASN66
P6 LEU

GLN155
ARG114
THR73
TRP133
LEU156
GLU152
TRP147
P7 SER

ASP77
THR73
GLU152
TRP147
ALA150
P8 GLY

LYS146
THR73
ASP77
TRP147
P9 LYS

ASP77
LYS146
ARG114
TYR84
TYR123
ILE95
ILE124
THR143
ILE97
THR80
TRP147
ASP116
ILE142
LEU81

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

LEU159
LEU163
CYS167
LEU171
SER5
GLY59
TRP63
GLU66
SER7
B Pocket

ARG24
THR34
SER45
TRP63
GLU66
THR67
SER7
VAL70
ARG9
GLN99
C Pocket

VAL70
GLN73
SER74
ARG9
THR97
D Pocket

ARG114
GLU155
ALA156
LEU159
ARG160
GLN99
E Pocket

ARG114
LYS147
ALA152
ALA156
THR97
F Pocket

TYR116
GLY123
ALA143
THR146
LYS147
ASP77
ASP80
LEU81
LEU84
SER95

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-A*03:01
IPD-IMGT/HLA
[ipd-imgt:HLA34773]
        10        20        30        40        50        60
MASGSHSMRYFFTSVSRPGRGEPRFIAVGYVDDTQFVRFDSDAASQRMEPRAPWIEQEGP
        70        80        90       100       110       120
EYWDQETRNVKAQSQTDRVDLGTLRGYYNQSEAGSHTIQIMYGCDVGSDGRFLRGYRQDA
       130       140       150       160       170       180
YDGKDYIALNEDLRSWTAADMAAQITKRKWEAAHEAEQLRAYLDGTCVEWLRRYLENGKE
       190       200       210       220       230       240
TLQRTDPPKTHMTHHPISDHEATLRCWALGFYPAEITLTWQRDGEDQTQDTELVETRPAG
       250       260       270       280       290
DGTFQKWAAVVVPSGEEQRYTCHVQHEGLPKPLTLRWELSSQPGSLHHILDAQKMVWNHR

3. Peptide
TTAPSLSGK


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.
Clicking on the clipboard icon will copy the url for the data to your clipboard.
This can then be used to load the structure/data directly from the url into an application like PyMol (for 3D structures) using the load command:
   e.g. load http://www.histo.fyi/structures/downloads/1hhk_1_peptide.cif
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. 6O9B assembly 1  

Components

MHC Class I alpha chain [cif]
  1. 6O9B assembly 1  
MHC Class I antigen binding domain (alpha1/alpha2) [cif]
  1. 6O9B assembly 1  
Peptide only [cif]
  1. 6O9B assembly 1  

Derived data

Data for this page [json]
https://api.histo.fyi/v1/structures/6o9b

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