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PDBsum entry 1t22
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Immune system
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PDB id
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1t22
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References listed in PDB file
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Key reference
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Title
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Structural basis for degenerate recognition of natural HIV peptide variants by cytotoxic lymphocytes.
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Authors
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E.Martinez-Hackert,
N.Anikeeva,
S.A.Kalams,
B.D.Walker,
W.A.Hendrickson,
Y.Sykulev.
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Ref.
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J Biol Chem, 2006,
281,
20205-20212.
[DOI no: ]
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PubMed id
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Abstract
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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.
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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%.
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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.
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The above figures are
reprinted
by permission from the ASBMB:
J Biol Chem
(2006,
281,
20205-20212)
copyright 2006.
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