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5ENW

HLA-A*02:01 binding "GLKEGIPAL" at 1.85Å 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*02:01
['A']
3. Peptide
GLKEGIPAL
['C']

Species


Locus / Allele group


Publication

Unconventional Peptide Presentation by Major Histocompatibility Complex (MHC) Class I Allele HLA-A*02:01: BREAKING CONFINEMENT.

Remesh SG, Andreatta M, Ying G, Kaever T, Nielsen M, McMurtrey C, Hildebrand W, Peters B, Zajonc DM
J. Biol. Chem. (2017) 292, 5262-5270 [doi:10.1074/jbc.M117.776542]  [pubmed:28179428

Peptide antigen presentation by major histocompatibility complex (MHC) class I proteins initiates CD8+ T cell-mediated immunity against pathogens and cancers. MHC I molecules typically bind peptides with 9 amino acids in length with both ends tucked inside the major A and F binding pockets. It has been known for a while that longer peptides can also bind by either bulging out of the groove in the middle of the peptide or by binding in a zigzag fashion inside the groove. In a recent study, we identified an alternative binding conformation of naturally occurring peptides from Toxoplasma gondii bound by HLA-A*02:01. These peptides were extended at the C terminus (PΩ) and contained charged amino acids not more than 3 residues after the anchor amino acid at PΩ, which enabled them to open the F pocket and expose their C-terminal extension into the solvent. Here, we show that the mechanism of F pocket opening is dictated by the charge of the first charged amino acid found within the extension. Although positively charged amino acids result in the Tyr-84 swing, amino acids that are negatively charged induce a not previously described Lys-146 lift. Furthermore, we demonstrate that the peptides with alternative binding modes have properties that fit very poorly to the conventional MHC class I pathway and suggest they are presented via alternative means, potentially including cross-presentation via the MHC class II pathway.

Structure deposition and release

Deposited: 2015-11-09
Released: 2016-11-09
Revised: 2018-05-09

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: GLKEGIPAL

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 GLY

PHE33
TYR59
TYR171
TYR159
TYR7
LYS66
GLU63
MET5
TRP167
P2 LEU

TRP167
GLU63
TYR99
HIS70
VAL67
PHE9
TYR159
TYR7
LYS66
MET45
P3 LYS

GLN155
LYS66
LEU156
TYR99
HIS70
TYR159
P4 GLU

LYS66
ARG65
P5 GLY

HIS70
P6 ILE

TYR99
HIS70
THR73
ARG97
HIS74
HIS114
P7 PRO

VAL152
THR73
ASP77
HIS114
TRP147
LEU156
ARG97
P8 ALA

THR73
ASP77
LYS146
TRP147
ARG97
VAL76
P9 LEU

LYS146
TRP147
TYR84
TYR123
ILE124
TYR116
LEU81
ASP77
THR80
THR143

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
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

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
IQRTPKIQVYSRHPAENGKSNFLNCYVSGFHPSDIEVDLLKNGERIEKVEHSDLSFSKDW
        70        80        90
SFYLLYYTEFTPTEKDEYACRVNHVTLSQPKIVKWDRDM

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
FQKWAAVVVPSGQEQRYTCHVQHEGLPKPLTLRW

3. Peptide
GLKEGIPAL


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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Complete structures

Aligned structures [cif]
  1. 5ENW assembly 1  

Components

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

Derived data

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

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