PDBsum entry 3cii

Immune system

PDB id: 3cii

Contents

Protein chains

273 a.a. *

100 a.a. *

121 a.a. *

116 a.a. *

Ligands

VAL-MET-ALA-PRO-ARG-THR-LEU-PHE-LEU ×2

* Residue conservation analysis

PDB id:

3cii

Name:

Immune system

Title:

Structure of nkg2a/cd94 bound to hla-e

Structure:

Hla class i histocompatibility antigen, alpha chain e. Chain: a, d. Fragment: ectodomain. Synonym: mhc class i antigen e. Engineered: yes. Beta-2-microglobulin. Chain: b, e. Engineered: yes. Hla class i histocompatibility antigen peptide.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: hla-e, hla-6.2, hlae. Expressed in: escherichia coli. Expression_system_taxid: 562. Gene: b2m, cdabp0092, hdcma22p. Synthetic: yes. Other_details: peptide is naturally found in humans and was

Resolution:

4.41Å R-factor: 0.321 R-free: 0.355

Authors:

R.K.Strong,B.K.Kaiser,J.C.Pizarro

Key ref:

B.K.Kaiser et al. (2008). Structural basis for NKG2A/CD94 recognition of HLA-E. Proc Natl Acad Sci U S A, 105, 6696-6701. PubMed id: 18448674 DOI: 10.1073/pnas.0802736105

Date:

11-Mar-08 Release date: 13-May-08

Protein chains

P13747  (HLAE_HUMAN) -  HLA class I histocompatibility antigen, alpha chain E from Homo sapiens

Seq: 358 a.a.

Struc: 273 a.a.*

Protein chains

P61769  (B2MG_HUMAN) -  Beta-2-microglobulin from Homo sapiens

Seq: 119 a.a.

Struc: 100 a.a.*

Protein chains

Q13241  (KLRD1_HUMAN) -  Natural killer cells antigen CD94 from Homo sapiens

Seq: 179 a.a.

Struc: 121 a.a.

Protein chains

P26715  (NKG2A_HUMAN) -  NKG2-A/NKG2-B type II integral membrane protein from Homo sapiens

Seq: 233 a.a.

Struc: 116 a.a.

* PDB and UniProt seqs differ at 2 residue positions (black crosses)

DOI no: 10.1073/pnas.0802736105

Proc Natl Acad Sci U S A 105:6696-6701 (2008)

PubMed id: 18448674

Structural basis for NKG2A/CD94 recognition of HLA-E.

B.K.Kaiser, J.C.Pizarro, J.Kerns, R.K.Strong.

ABSTRACT

The NKG2x/CD94 (x = A, C, E) natural killer-cell receptors perform an important role in immunosurveillance by binding to HLA-E complexes that exclusively present peptides derived from MHC class I leader sequences, thereby monitoring MHC class I expression. We have determined the crystal structure of the NKG2A/CD94/HLA-E complex at 4.4-A resolution, revealing two critical aspects of this interaction. First, the C-terminal region of the peptide, which displays the most variability among class I leader sequences, interacts entirely with CD94, the invariant component of these receptors. Second, residues 167-170 of NKG2A/C account for the approximately 6-fold-higher affinity of the inhibitory NKG2A/CD94 receptor compared to its activating NKG2C/CD94 counterpart. These residues do not contact HLA-E or peptide directly but instead form part of the heterodimer interface with CD94. An evolutionary analysis across primates reveals that whereas CD94 is evolving under purifying selection, both NKG2A and NKG2C are evolving under positive selection. Specifically, residues at the CD94 interface have evolved under positive selection, suggesting that the evolution of these genes is driven by an interaction with pathogen-derived ligands. Consistent with this possibility, we show that NKG2C/CD94, but not NKG2A/CD94, weakly but specifically binds to the CMV MHC-homologue UL18. Thus, the evolution of the NKG2x/CD94 family of receptors has likely been shaped both by the need to bind the invariant HLA-E ligand and the need to avoid subversion by pathogen-derived decoys.

Selected figure(s)

Figure 1.
The NKG2A/CD94/HLA-E complex structure. (A and B) Ribbon representations of the complex viewed from the side (A) or from above (B), colored by chain [NKG2A: red; CD94: green; HLA-E heavy chain: blue; β[2]m: purple; peptide (showing all atoms): yellow]. (C) Superpositions of α-carbon backbone traces of NKG2A/CD94 crystallized in complex with HLA-E (showing the de novo-built NKG2A model; NKG2A: dark green; CD94: dark red) and alone (NKG2A: pale green; CD94: pale red; ref. 12). The superpositions were aligned on CD94. Note that the structure of the receptor in the complex includes residues 200–203 that are absent from the free structure. (D) A schematic representation of the contacts between NKG2A (red spheres)/CD94 (green spheres) and HLA-E α1 (light blue) and α2 (dark blue) domains. An asterisk indicates residues (HLA-E^R65, HLA-E^R79, HLA-E^E166, NKG2A^R215) that are predicted to be involved in binding by mutagenesis (12) but are not contacts in the structure.

Figure 3.
Contacts between NKG2A/CD94 and HLA-E/peptide. (A) Molecular surface representations are shown of NKG2A (red), CD94 (green), and HLA-E (blue), with the peptide shown in an all-atom representation (N terminus on the left). The complex has been splayed open to reveal the interface, with regions on each half of the complex colored by the molecule making reciprocal contacts. Coils have been included on the right to indicate the position of the HLA-E α-helices from the complex relative to NKG2A/CD94. (B) Contacts between NKG2A/CD94 (Left) or TCR KK50.4 (Right) and HLA-E are shown, with the molecules shown as ribbons, colored as in A. The TCR α chain is purple, and the TCR β chain is green. (C) The complex is shown as in A, but with interface residues colored by a heat map (mutations with >10-fold effect on affinity: red for HLA-E or salmon for CD94; 3- to 5-fold effect: yellow; 2-fold or less: blue) based on the previous alanine mutagenesis analysis (12). (D) Schematic representation of the binding footprints of NKG2A/CD94 (yellow) and TCR KK50.4 (blue) on HLA-E.

Figures were selected by an automated process.