PDBsum entry 1t22

Immune system

PDB id: 1t22

Contents

Protein chains

275 a.a. *

99 a.a. *

Ligands

SER-LEU-TYR-ASN-THR-VAL-ALA-THR-LEU

Waters ×356

* Residue conservation analysis

PDB id:

1t22

Name:

Immune system

Title:

Structural basis for degenerate recognition of HIV peptide variants by cytotoxic lymphocyte, variant sl9, orthorhombic crystal

Structure:

Hla class i histocompatibility antigen, a-2 alpha chain. Chain: a. Synonym: mhc class i antigen a 2, Hla-a2. Engineered: yes. Beta-2-microglobulin. Chain: b. Synonym: hdcma22p. Engineered: yes. Gag peptide.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: hla-a, hlaa. Expressed in: drosophila melanogaster. Expression_system_taxid: 7227. Gene: b2m. Synthetic: yes. Other_details: the peptide was chemically synthesized. The sequence

Biol. unit:

Trimer (from PQS)

Resolution:

2.20Å R-factor: 0.184 R-free: 0.231

Authors:

E.Martinez-Hackert,N.Anikeeva,S.A.Kalams,B.D.Walker,W.A.Hendrickson, Y.Sykulev

Key ref:

E.Martinez-Hackert et al. (2006). Structural basis for degenerate recognition of natural HIV peptide variants by cytotoxic lymphocytes. J Biol Chem, 281, 20205-20212. PubMed id: 16702212 DOI: 10.1074/jbc.M601934200

Date:

19-Apr-04 Release date: 06-Sep-05

Protein chain

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

Seq: 365 a.a.

Struc: 275 a.a.*

Protein chain

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

Seq: 119 a.a.

Struc: 99 a.a.

* PDB and UniProt seqs differ at 19 residue positions (black crosses)

DOI no: 10.1074/jbc.M601934200

J Biol Chem 281:20205-20212 (2006)

PubMed id: 16702212

Structural basis for degenerate recognition of natural HIV peptide variants by cytotoxic lymphocytes.

E.Martinez-Hackert, N.Anikeeva, S.A.Kalams, B.D.Walker, W.A.Hendrickson, Y.Sykulev.

ABSTRACT

It is well established that even small changes in amino acid side chains of antigenic peptide bound to major histocompatibility complex (MHC) protein may completely abrogate recognition of the peptide-MHC (pMHC) complex by the T cell receptor (TCR). Often, however, several nonconservative substitutions in the peptide antigen are accommodated and do not impair its recognition by TCR. For example, a preponderance of natural sequence variants of the human immunodeficiency virus p17 Gag-derived peptide SLYNTVATL (SL9) are recognized by cytotoxic T lymphocytes, which implies that interactions with SL9 variants are degenerate both with respect to the class I MHC molecule and with respect to TCR. Here we study the molecular basis for this degenerate recognition of SL9 variants. We show that several SL9 variants bind comparably well to soluble HLA-A2 and to a particular soluble TCR and that these variants are active in the cognate cytotoxicity assay. Natural SL9 variation is restricted by its context in the HIV p17 matrix protein. High resolution crystal structures of seven selected SL9 variants bound to HLA-A2 all have remarkably similar peptide conformations and side-chain dispositions outside sites of substitution. This preservation of the peptide conformation despite epitope variations suggests a mechanism for the observed degeneracy in pMHC recognition by TCR and may contribute to the persistence of SL9-mediated immune responses in chronically infected individuals.

Selected figure(s)

Figure 2.
FIGURE 2. Binding of HLA-A2/tetramer loaded with SL9 peptide variants to immobilized D3 TCR. The tetramer concentrations (DR[50]) that produced half-maximal response (designated by the dotted line) are presented in Table 1. A representative result of at least three independent experiments is shown. Each tetramer concentration was tested in triplicate. Deviations of absorbance (OD, 490) in triplicate did not exceed 7%.

Figure 3.
FIGURE 3. SL9 peptides bound to HLA-A2. a, simulated (F[o] – F[c]) omit map of SL9 peptide bound to HLA-A2. Electron density within 5 Å of the peptide is contoured at the 2 level. Polypeptide backbones of the [1] (gold) and [2](blue) chains of HLA-A2 are indicated by ribbon diagram. b, CPK model of the SL9 peptide built into the molecular surface of HLA-A2 rendered with convexity increasingly green and concavity increasingly gray. c, the SL9-A3-HLA-A2 complex presented as in b. Loss of the aromatic ring upon substitution of alanine for tyrosine in P3 (position marked by arrows) leads to a cavity on the MHC surface. Concomitantly, there is a complete loss of detectable interaction between SL9-A3-HLA-A2 and D3.

The above figures are reprinted by permission from the ASBMB: J Biol Chem (2006, 281, 20205-20212) copyright 2006.

Figures were selected by the author.