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PDBsum entry 2ial
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Immune system
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PDB id
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2ial
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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 the recognition of mutant self by a tumor-Specific, Mhc class ii-Restricted t cell receptor.
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Authors
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L.Deng,
R.J.Langley,
P.H.Brown,
G.Xu,
L.Teng,
Q.Wang,
M.I.Gonzales,
G.G.Callender,
M.I.Nishimura,
S.L.Topalian,
R.A.Mariuzza.
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Ref.
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Nat Immunol, 2007,
8,
398-408.
[DOI no: ]
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PubMed id
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Abstract
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Structural studies of complexes of T cell receptor (TCR) and peptide-major
histocompatibility complex (MHC) have focused on TCRs specific for foreign
antigens or native self. An unexplored category of TCRs includes those specific
for self determinants bearing alterations resulting from disease, notably
cancer. We determined here the structure of a human melanoma-specific TCR (E8)
bound to the MHC molecule HLA-DR1 and an epitope from mutant triosephosphate
isomerase. The structure had features intermediate between 'anti-foreign' and
autoimmune TCR-peptide-MHC class II complexes that may reflect the hybrid nature
of altered self. E8 manifested very low affinity for mutant triosephosphate
isomerase-HLA-DR1 despite the highly tumor-reactive properties of E8 cells. A
second TCR (G4) had even lower affinity but underwent peptide-specific formation
of dimers, suggesting this as a mechanism for enhancing low-affinity
TCR-peptide-MHC interactions for T cell activation.
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Figure 4.
(a) TCR residues in contact with mutant TPI. The substituted
TPI isoleucine residue (position 3) is magenta. (b) Interactions
between E8 and mutant TPI. (c) Interactions between the E8 V[
 ]domain
and the HLA-DR1  1
 -helix.
(d,e) Interactions between mutant TPI isoleucine at position 3
and TCR E8 (d) or wild-type TPI threonine at position 3 and
HLA-DR1 complexes (e). TCR residues are identified by one-letter
amino-acid designation followed by position number and chain
designation; peptide residues are identified by one-letter
amino-acid designation followed by position ('P') number. Colors
of TCR and MHC molecules as in Figure 3; hydrogen bonds, red
dotted lines; salt bridges, solid lines; van der Waals contacts,
black dotted lines.
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Figure 6.
(a–c) Structural rearrangements in CDR2 ,
CDR3 and
CDR3 induced
by binding to mutant TPI–DR1. Bound E8, green; unbound E8,
magenta; HLA-DR1, gold; mutant TPI, gray. Residues from E8 and
DR1 involved in interactions with peptide are identified. (d)
Superposition of mutant TPI–DR1 in a form without bound ligand
(peptide, cyan; MHC, violet) and in complex with E8 (peptide,
gray; MHC, gold). Arrow indicates residues 55–59 of the
HLA-DR1 1
domain. (e) Conformational changes in TPI residues that contact
E8. Residues of TPI involved in interactions with E8 are
identified. Residue designations as in Figure 4.
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The above figures are
reprinted
by permission from Macmillan Publishers Ltd:
Nat Immunol
(2007,
8,
398-408)
copyright 2007.
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