4WUU

HLA-A*02:01 binding "RMFPNAPYL" with antibody at 3.05Å 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

['E']

2. ab_light

['D']

3. Beta 2 microglobulin

['B']

4. Class I alpha
HLA-A*02:01

['A']

5. Peptide
RMFPNAPYL

['C']

Species

Homo sapiens (Human)

Locus / Allele group

HLA-A / HLA-A*02

Publication

Structure of a TCR mimic antibody with target predicts pharmacogenetics.

Ataie N, Xiang J, Cheng N, Brea EJ, Lu W, Scheinberg DA, Liu C, Ng HL

J. Mol. Biol. (2015) [doi:10.1016/j.jmb.2015.12.002] [pubmed:26688548]

Antibody therapies currently target only extracellular antigens. A strategy to recognize intracellular antigens is to target peptides presented by immune HLA receptors. ESK1 is a human, T-cell receptor (TCR)-mimic antibody that binds with subnanomolar affinity to the RMF peptide from the intracellular Wilms tumor oncoprotein WT1 in complex with HLA-A*02:01. ESK1 is therapeutically effective in mouse models of WT1(+) human cancers. TCR-based therapies have been presumed to be restricted to one HLA subtype. The mechanism for the specificity and high affinity of ESK1 is unknown. We show in a crystal structure that ESK1 Fab binds to RMF/HLA-A*02:01 in a mode different from that of TCRs. From the structure, we predict and then experimentally confirm high-affinity binding with multiple other HLA-A*02 subtypes, broadening the potential patient pool for ESK1 therapy. Using the crystal structure, we also predict potential off-target binding that we experimentally confirm. Our results demonstrate how protein structure information can contribute to personalized immunotherapy.

Structure deposition and release

Deposited: 2014-11-03

Released: 2015-12-30

Revised: 2016-02-10

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: RMFPNAPYL

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 ARG

CYS164

TYR59

TYR7

TRP167

TYR99

GLU63

THR163

PHE33

MET5

TYR171

TYR159

LYS66

P2 MET

HIS70

MET45

GLU63

VAL67

THR64

VAL34

GLY62

TYR159

TYR7

LYS66

TYR99

PHE9

THR163

P3 PHE

TYR7

HIS114

LEU156

TYR99

VAL152

HIS70

TYR159

GLN155

ARG97

LYS66

P4 PRO

ALA69

TYR159

LYS66

THR163

HIS70

P5 ASN

HIS70

GLN155

ARG97

P6 ALA

ALA69

TYR116

THR73

HIS74

HIS70

ASP77

ARG97

P7 PRO

LEU156

VAL152

TRP147

ARG97

TYR116

THR73

ASP77

HIS114

P8 TYR

VAL76

LYS146

TRP147

THR73

THR80

THR143

ASP77

GLN72

P9 LEU

TYR84

TYR123

VAL95

LYS146

ILE124

TRP147

TYR116

THR73

HIS74

LEU81

THR142

THR80

THR143

ASP77

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

GLY63

ARG66

ARG7

B Pocket

ILE24

PHE34

ARG45

GLY63

ARG66

LYS67

ARG7

ALA70

PHE9

MET99

C Pocket

ALA70

GLN73

THR74

PHE9

GLN97

D Pocket

TYR114

GLU155

GLN156

ALA159

TYR160

MET99

E Pocket

TYR114

LYS147

HIS152

GLN156

GLN97

F Pocket

GLN116

ASP123

THR143

HIS146

LYS147

VAL77

GLY80

THR81

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 QMQLVQSGAEVKEPGESLRISCKGSGYSFTNFWISWVRQMPGKGLEWMGRVDPGYSYSTY 70 80 90 100 110 120 SPSFQGHVTISADKSTSTAYLQWNSLKASDTAMYYCARVQYSGYYDWFDPWGQGTLVTVS 130 140 150 160 170 180 SASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQS 190 200 210 220 SGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKS

2. ab_light ab_light	10 20 30 40 50 60 QAVVTQPPSASGTPGQRVTISCSGSSSNIGSNTVNWYQQVPGTAPKLLIYSNNQRPSGVP 70 80 90 100 110 120 DRFSGSKSGTSASLAISGLQSEDEADYYCAAWDDSLNGWVFGGGTKLTVLGQPKANPTVT 130 140 150 160 170 180 LFPPSSEELQANKATLVCLISDFYPGAVTVAWKADGSPVKAGVETTKPSKQSNNKYAASS 190 200 210 YLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS

3. Beta 2 microglobulin Beta 2 microglobulin	10 20 30 40 50 60 MIQRTPKIQVYSRHPAENGKSNFLNCYVSGFHPSDIEVDLLKNGERIEKVEHSDLSFSKD 70 80 90 WSFYLLYYTEFTPTEKDEYACRVNHVTLSQPKIVKWDRDM

4. Class I alpha HLA-A02:01 IPD-IMGT/HLA* [ipd-imgt:HLA35266]	10 20 30 40 50 60 MGSHSMRYFFTSVSRPGRGEPRFIAVGYVDDTQFVRFDSDAASQRMEPRAPWIEQEGPEY 70 80 90 100 110 120 WDGETRKVKAHSQTHRVDLGTLRGYYNQSEAGSHTVQRMYGCDVGSDWRFLRGYHQYAYD 130 140 150 160 170 180 GKDYIALKEDLRSWTAADMAAQTTKHKWEAAHVAEQLRAYLEGTCVEWLRRYLENGKETL 190 200 210 220 230 240 QRTDAPKTHMTHHAVSDHEATLRCWALSFYPAEITLTWQRDGEDQTQDTELVETRPAGDG 250 260 270 280 290 TFQKWAAVVVPSGQEQRYTCHVQHEGLPKPLTLRWEPGSGGGLNDIFEAQKIGWHE

5. Peptide	RMFPNAPYL

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]

4WUU assembly 1

Components

MHC Class I alpha chain [cif]

4WUU assembly 1

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

4WUU assembly 1

Peptide only [cif]

4WUU assembly 1

Derived data

Data for this page [json]

https://api.histo.fyi/v1/structures/4wuu

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.