6W51

HLA-A*02:01 binding "HMTEVVRHC" with antibody at 3.53Å 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

['S']

2. ab_light

['T']

3. Beta 2 microglobulin

['B', 'E', 'H', 'K']

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

['A', 'D', 'G', 'J']

5. Peptide
HMTEVVRHC

['C', 'F', 'I', 'L']

Species

Homo sapiens (Human)

Locus / Allele group

HLA-A / HLA-A*02

Publication

Targeting a neoantigen derived from a common TP53 mutation.

Hsiue EH, Wright KM, Douglass J, Hwang MS, Mog BJ, Pearlman AH, Paul S, DiNapoli SR, Konig MF, Wang Q, Schaefer A, Miller MS, Skora AD, Azurmendi PA, Murphy MB, Liu Q, Watson E, Li Y, Pardoll DM, Bettegowda C, Papadopoulos N, Kinzler KW, Vogelstein B, Gabelli SB, Zhou S

Science (2021) 371, [doi:10.1126/science.abc8697] [pubmed:33649166]

TP53 (tumor protein p53) is the most commonly mutated cancer driver gene, but drugs that target mutant tumor suppressor genes, such as TP53, are not yet available. Here, we describe the identification of an antibody highly specific to the most common TP53 mutation (R175H, in which arginine at position 175 is replaced with histidine) in complex with a common human leukocyte antigen-A (HLA-A) allele on the cell surface. We describe the structural basis of this specificity and its conversion into an immunotherapeutic agent: a bispecific single-chain diabody. Despite the extremely low p53 peptide-HLA complex density on the cancer cell surface, the bispecific antibody effectively activated T cells to lyse cancer cells that presented the neoantigen in vitro and in mice. This approach could in theory be used to target cancers containing mutations that are difficult to target in conventional ways.

Structure deposition and release

Deposited: 2020-03-12

Released: 2021-03-17

Revised: 2021-03-17

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: HMTEVVRHC

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 HIS

TYR159

TYR59

LYS66

THR163

TRP167

TYR7

TYR171

GLU63

PHE33

MET5

P2 MET

VAL67

PHE9

GLU63

TYR99

ALA24

TYR159

LYS66

HIS70

MET45

TYR7

P3 THR

LEU156

HIS70

TYR99

TYR159

LYS66

P4 GLU

ARG65

LYS66

HIS70

P5 VAL

HIS114

LEU156

GLN155

TYR159

VAL152

P6 VAL

THR73

ARG97

HIS70

ALA69

P7 ARG

ARG97

ALA150

LYS146

THR73

VAL152

TRP147

ASP77

P8 HIS

VAL76

LYS146

THR73

TRP147

ASP77

P9 CYS

THR143

TYR123

LYS146

TYR116

LEU81

TRP147

ASP77

THR80

TYR84

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 EVQLVESGGGLVQPGGSLRLSCAASGFNVYASGMHWVRQAPGKGLEWVAKIYPDSDYTYY 70 80 90 100 110 120 ADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRDSSFYYVYAMDYWGQGTLVTVS 130 140 150 160 170 180 SASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQS 190 200 210 220 SGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKS

2. ab_light ab_light	10 20 30 40 50 60 DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSAYFLYSGVPS 70 80 90 100 110 120 RFSGSRSGTDFTLTISSLQPEDFATYYCQQYSRYSPVTFGQGTKVEIKRTVAAPSVFIFP 130 140 150 160 170 180 PSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTL 190 200 210 TLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

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-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 TFQKWAAVVVPSGQEQRYTCHVQHEGLPKPLTLRWEPGSGSGLNDIFEAQKIEWHE

5. Peptide	HMTEVVRHC

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]

6W51 assembly 1

Components

MHC Class I alpha chain [cif]

6W51 assembly 1

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

6W51 assembly 1

Peptide only [cif]

6W51 assembly 1

Derived data

Data for this page [json]

https://api.histo.fyi/v1/structures/6w51

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.