5KNM

HLA-F*01:01 binding "ILRWEQ" with LIR-1 NK receptor at 3.30Å 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 lir1

1. Beta 2 microglobulin

['B']

2. Class I alpha
HLA-F*01:01

['A']

3. LIR-1

['D']

4. Peptide
ILRWEQ

['N']

Species

Homo sapiens (Human)

Locus / Allele group

HLA-F / HLA-F*01

Publication

Human Leukocyte Antigen F Presents Peptides and Regulates Immunity through Interactions with NK Cell Receptors.

Dulberger CL, McMurtrey CP, Hölzemer A, Neu KE, Liu V, Steinbach AM, Garcia-Beltran WF, Sulak M, Jabri B, Lynch VJ, Altfeld M, Hildebrand WH, Adams EJ

Immunity (2017) 46, 1018-1029.e7 [doi:10.1016/j.immuni.2017.06.002] [pubmed:28636952]

Evidence is mounting that the major histocompatibility complex (MHC) molecule HLA-F (human leukocyte antigen F) regulates the immune system in pregnancy, infection, and autoimmunity by signaling through NK cell receptors (NKRs). We present structural, biochemical, and evolutionary analyses demonstrating that HLA-F presents peptides of unconventional length dictated by a newly arisen mutation (R62W) that has produced an open-ended groove accommodating particularly long peptides. Compared to empty HLA-F open conformers (OCs), HLA-F tetramers bound with human-derived peptides differentially stained leukocytes, suggesting peptide-dependent engagement. Our in vitro studies confirm that NKRs differentiate between peptide-bound and peptide-free HLA-F. The complex structure of peptide-loaded β₂m-HLA-F bound to the inhibitory LIR1 revealed similarities to high-affinity recognition of the viral MHC-I mimic UL18 and a docking strategy that relies on contacts with HLA-F as well as β₂m, thus precluding binding to HLA-F OCs. These findings provide a biochemical framework to understand how HLA-F could regulate immunity via interactions with NKRs.

Structure deposition and release

Deposited: 2016-06-28

Released: 2017-06-14

Revised: 2020-07-29

Data provenance

Publication data retrieved from PDBe REST API8 and PMCe REST API9

Other structures from this publication

Peptide details

Length: Hexamer (6 amino acids)

Sequence: ILRWEQ

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

P2 ILE

TYR66

TRP62

P3 LEU

TYR66

ASN70

ALA69

P4 ARG

TYR159

TYR7

TYR66

ASN70

TYR152

PHE156

GLU155

ASN99

P5 TRP

PHE8

ASP74

GLY97

HIS116

THR73

ASN99

TYR7

TYR66

ASN70

SER9

HIS114

TYR152

MET98

P6 GLU

HIS114

TYR152

TYR147

GLU150

P7 GLN

TYR147

HIS114

ALA77

THR143

ASP74

HIS116

THR73

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

GLU163

LEU167

TYR171

LEU5

TYR59

THR63

TYR66

TYR7

B Pocket

ALA24

LEU34

MET45

THR63

TYR66

ALA67

TYR7

ASN70

SER9

ASN99

C Pocket

ASN70

THR73

ASP74

SER9

GLY97

D Pocket

HIS114

GLU155

PHE156

TYR159

LEU160

ASN99

E Pocket

HIS114

TYR147

TYR152

PHE156

GLY97

F Pocket

HIS116

TYR123

THR143

PHE146

TYR147

ALA77

ASN80

LEU81

ARG84

LEU95

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 MLLVNQSHQGFNKEHTSKMVSAIVLYVLLAAAAHSAFAADLHHHHHHHHGSGGLEVLFQG 70 80 90 100 110 120 PEFGGSADPIQRTPKIQVYSRHPAENGKSNFLNCYVSGFHPSDIEVDLLKNGERIEKVEH 130 140 150 160 170 180 SDLSFSKDWSFYLLYYTEFTPTEKDEYACRVNHVTLSQPKIVKWDRDMGGGGSGGSGSGG GS

2. Class I alpha HLA-F01:01 IPD-IMGT/HLA* [ipd-imgt:HLA35225]	10 20 30 40 50 60 GSHSLRYFSTAVSRPGRGEPRYIAVEYVDDTQFLRFDSDAAIPRMEPREPWVEQEGPQYW 70 80 90 100 110 120 EWTTGYAKANAQTDRVALRNLLRRYNQSEAGSHTLQGMNGCDMGPDGRLLRGYHQHAYDG 130 140 150 160 170 180 KDYISLNEDLRSWTAADTVAQITQRFYEAEEYAEEFRTYLEGECLELLRRYLENGKETLQ 190 200 210 220 230 240 RADPPKAHVAHHPISDHEATLRCWALGFYPAEITLTWQRDGEEQTQDTELVETRPAGDGT 250 260 270 280 FQKWAAVVVPSGEEQRYTCHVQHEGLPQPLILRWEQSPQPTIPI

3. LIR-1 LIR-1	10 20 30 40 50 60 MLLVNQSHQGFNKEHTSKMVSAIVLYVLLAAAAHSAFAADLHHHHHHHHGSGGLEVLFQG 70 80 90 100 110 120 PEFGGSADLGHLPKPTLWAEPGSVITQGSPVTLRCQGGQETQEYRLYREKKTALWITRIP 130 140 150 160 170 180 QELVKKGQFPIPSITWEHAGRYRCYYGSDTAGRSESSDPLELVVTGAYIKPTLSAQPSPV 190 200 210 220 230 240 VNSGGNVILQCDSQVAFDGFSLCKEGEDEHPQCLNSQPHARGSSRAIFSVGPVSPSRRWW 250 260 YRCYAYDSNSPYEWSLPSDLLELLVLG

4. Peptide	ILRWEQ

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]

5KNM assembly 1

Components

MHC Class I alpha chain [cif]

5KNM assembly 1

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

5KNM assembly 1

Peptide only [cif]

5KNM assembly 1

Derived data

Data for this page [json]

https://api.histo.fyi/v1/structures/5knm

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.