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PDBsum entry 2git
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Immune system
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PDB id
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2git
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References listed in PDB file
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Key reference
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Title
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T cell receptor recognition via cooperative conformational plasticity.
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Authors
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S.J.Gagnon,
O.Y.Borbulevych,
R.L.Davis-Harrison,
R.V.Turner,
M.Damirjian,
A.Wojnarowicz,
W.E.Biddison,
B.M.Baker.
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Ref.
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J Mol Biol, 2006,
363,
228-243.
[DOI no: ]
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PubMed id
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Abstract
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Although T cell receptor cross-reactivity is a fundamental property of the
immune system and is implicated in numerous autoimmune pathologies, the
molecular mechanisms by which T cell receptors can recognize and respond to
diverse ligands are incompletely understood. In the current study we examined
the response of the human T cell lymphotropic virus-1 (HTLV-1) Tax-specific T
cell receptor (TCR) A6 to a panel of structurally distinct haptens coupled to
the Tax 11-19 peptide with a lysine substitution at position 5 (Tax5K,
LLFG[K-hapten]PVYV). The A6 TCR could cross-reactively recognize one of these
haptenated peptides, Tax-5K-4-(3-Indolyl)-butyric acid (IBA), presented by
HLA-A*0201. The crystal structures of Tax5K-IBA/HLA-A2 free and in complex with
A6 reveal that binding is mediated by a mechanism of cooperative conformational
plasticity involving conformational changes on both sides of the protein-protein
interface, including the TCR complementarity determining region (CDR) loops,
Valpha/Vbeta domain orientation, and the hapten-modified peptide. Our findings
illustrate the complex role that protein dynamics can play in TCR
cross-reactivity and highlight that T cell receptor recognition of ligand can be
achieved through diverse and complex molecular mechanisms that can occur
simultaneously in the interface, not limited to molecular mimicry and CDR loop
shifts.
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Figure 1.
Figure 1. The native Tax peptide (top) and the Tax-5K-IBA
peptide (bottom), illustrating the chemical and structural
differences between the two position 5 side-chains.
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Figure 5.
Figure 5. Stereo views of accommodation of the P5
side-chains by the A6 TCR. (a) In the ternary complex, the
Lys-IBA side-chain bends around towards the HLA-A2 α2 helix and
fits between the A6 CDR3α and CDR3β loops. The peptide is
shown in magenta along with 2F[o]–F[c] electron density
contoured at 1σ. CDR3β of A6 is in yellow, CDR3α is green;
other TCR components are not shown. Three hydrogen bonds are
formed between the Lys-IBA side-chain and Arg95 and Gly101 of
CDR3β (indicated as hb1, hb2, and hb3). A fourth hydrogen bond
(hb4) is formed between the IBA moiety and Gln155 of HLA-A2
(orange). (b) In the structure with the native Tax peptide, the
Tyr at P5 fits into a pocket generated by the juxtaposition of
CDR3β (blue) and CDR3α (yellow). (c) In the structure with the
Tax-5K-IBA peptide, changes in the CDR3 loops and the shift in
Vα/Vβ orientation greatly expand the central pocket in order
to accommodate the larger side-chain.
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The above figures are
reprinted
by permission from Elsevier:
J Mol Biol
(2006,
363,
228-243)
copyright 2006.
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