PDBsum entry 2gtw

Immune system

PDB id: 2gtw

Contents

Protein chains

275 a.a. *

100 a.a. *

Ligands

LEU-ALA-GLY-ILE-GLY-ILE-LEU-THR-VAL ×2

GOL ×5

FMT ×4

Metals

_NA ×2

Waters ×672

* Residue conservation analysis

PDB id:

2gtw

Name:

Immune system

Title:

Human class i mhc hla-a2 in complex with the nonameric melan-a/mart- 1(27-35) peptide having a27l substitution

Structure:

Hla-a 0201 Heavy chain. Chain: a, d. Fragment: heavy chain. Synonym: hla class i histocompatibility antigen, a-2 alpha chain. Mhc class i antigen a 2. Engineered: yes. Beta-2-microglobulin. Chain: b, e. Synonym: beta-2-microglobulin variant pi 5.3.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: hla-a. Expressed in: escherichia coli bl21. Expression_system_taxid: 511693. Gene: b2m. Synthetic: yes. Other_details: commercial synthesis for the peptide

Resolution:

1.55Å R-factor: 0.183 R-free: 0.218

Authors:

O.Y.Borbulevych,B.M.Baker

Key ref:

O.Y.Borbulevych et al. (2007). Structures of MART-1(26/27-35) Peptide/HLA-A2 Complexes Reveal a Remarkable Disconnect between Antigen Structural Homology and T Cell Recognition. J Mol Biol, 372, 1123-1136. PubMed id: 17719062 DOI: 10.1016/j.jmb.2007.07.025

Date:

28-Apr-06 Release date: 12-Jun-07

Protein chains

P04439  (1A03_HUMAN) -  HLA class I histocompatibility antigen, A alpha chain from Homo sapiens

Seq: 365 a.a.

Struc: 275 a.a.*

Protein chains

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

Seq: 119 a.a.

Struc: 100 a.a.*

* PDB and UniProt seqs differ at 20 residue positions (black crosses)

DOI no: 10.1016/j.jmb.2007.07.025

J Mol Biol 372:1123-1136 (2007)

PubMed id: 17719062

Structures of MART-1(26/27-35) Peptide/HLA-A2 Complexes Reveal a Remarkable Disconnect between Antigen Structural Homology and T Cell Recognition.

O.Y.Borbulevych, F.K.Insaidoo, T.K.Baxter, D.J.Powell, L.A.Johnson, N.P.Restifo, B.M.Baker.

ABSTRACT

Small structural changes in peptides presented by major histocompatibility complex (MHC) molecules often result in large changes in immunogenicity, supporting the notion that T cell receptors are exquisitely sensitive to antigen structure. Yet there are striking examples of TCR recognition of structurally dissimilar ligands. The resulting unpredictability of how T cells will respond to different or modified antigens impacts both our understanding of the physical bases for TCR specificity as well as efforts to engineer peptides for immunomodulation. In cancer immunotherapy, epitopes and variants derived from the MART-1/Melan-A protein are widely used as clinical vaccines. Two overlapping epitopes spanning amino acid residues 26 through 35 are of particular interest: numerous clinical studies have been performed using variants of the MART-1 26-35 decamer, although only the 27-35 nonamer has been found on the surface of targeted melanoma cells. Here, we show that the 26-35 and 27-35 peptides adopt strikingly different conformations when bound to HLA-A2. Nevertheless, clonally distinct MART-1(26/27-35)-reactive T cells show broad cross-reactivity towards these ligands. Simultaneously, however, many of the cross-reactive T cells remain unable to recognize anchor-modified variants with very subtle structural differences. These dichotomous observations challenge our thinking about how structural information on unligated peptide/MHC complexes should be best used when addressing questions of TCR specificity. Our findings also indicate that caution is warranted in the design of immunotherapeutics based on the MART-1 26/27-35 epitopes, as neither cross-reactivity nor selectivity is predictable based on the analysis of the structures alone.

Selected figure(s)

Figure 1.
Figure 1. MART-1[26/27–35]-based peptides adopt one of two general conformations in the HLA-A2 peptide-binding groove. (a) Superimposition of the native AAG nonamer and the P2-modified ALG nonamer solved here and by Sliz et al.,^24 identifying the extended conformation. (b) Superimposition of the native EAA decamer, the P2-modified ELA decamer solved by Sliz et al., and the P1-modified LAG nonamer, identifying the bulged conformation. (c) Stereo image comparing the extended conformation of the native AAG nonamer and the bulged conformation of the ELA decamer. (d) Same as in (c), but rotated 90° out and showing the surface of HLA-A2 as partially transparent. All superimpositions are via the backbones of P1 and P6−P9.

Figure 2.
Figure 2. Quantitative comparison of the conformations of the various MART-1[26/27–35]-based peptides. The Figure shows the pair-wise superimposition matrix of all conformations of the peptides, including both molecules in each asymmetric unit for the structures solved here (MOL 1 and MOL 2), the two alternative conformations for the ALG nonamer (MOL 1A and MOL 1B), and the ALG and ELA structures of Sliz et al.^24 Values are RMSD in Å. Superimpositions are via the backbones of P1−P9 (the first amino acid residue in the decameric peptides is P0). Values for peptides in the extended conformation (AAG and ALG) are green; values for peptides in the bulged conformation (EAA, ELA, and LAG) are blue. Cross-conformational superimpositions are red. Superimpositions of two molecules in the asymmetric units of any one structure (i.e. MOL 1 onto MOL 2) are shaded grey. It is of note that the cross-conformational superimpositions are all close to 2 Å, reflecting the differences between the bulged and extended conformations.

The above figures are reprinted from an Open Access publication published by Elsevier: J Mol Biol (2007, 372, 1123-1136) copyright 2007.

Figures were selected by an automated process.