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PDBsum entry 2gtw
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Immune system
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PDB id
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2gtw
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References listed in PDB file
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Key reference
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Title
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Structures of mart-1(26/27-35) peptide/hla-A2 complexes reveal a remarkable disconnect between antigen structural homology and t cell recognition.
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Authors
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O.Y.Borbulevych,
F.K.Insaidoo,
T.K.Baxter,
D.J.Powell,
L.A.Johnson,
N.P.Restifo,
B.M.Baker.
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Ref.
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J Mol Biol, 2007,
372,
1123-1136.
[DOI no: ]
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PubMed id
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Abstract
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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.
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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.
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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.
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The above figures are
reprinted
from an Open Access publication published by Elsevier:
J Mol Biol
(2007,
372,
1123-1136)
copyright 2007.
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