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* Residue conservation analysis
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J Immunol
174:4812-4820
(2005)
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PubMed id:
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Increased immunogenicity of an anchor-modified tumor-associated antigen is due to the enhanced stability of the peptide/MHC complex: implications for vaccine design.
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O.Y.Borbulevych,
T.K.Baxter,
Z.Yu,
N.P.Restifo,
B.M.Baker.
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ABSTRACT
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The use of "anchor-fixed" altered peptide ligands is of considerable interest in
the development of therapeutic vaccines for cancer and infectious diseases, but
the mechanism by which successful altered peptide ligands elicit enhanced
immunity is unclear. In this study, we have determined the crystallographic
structure of a major tumor rejection Ag, gp100(209-217), in complex with the
HLA-A*0201 (HLA-A2) molecule, as well as the structure of a modified version of
the peptide which substitutes methionine for threonine at position 2 (T2M;
gp100(209-2M)). The T2M-modified peptide, which is more immunogenic in vitro and
in vivo, binds HLA-A2 with a approximately 9-fold greater affinity and has a
approximately 7-fold slower dissociation rate at physiological temperature.
Within the limit of the crystallographic data, the T2M substitution does not
alter the structure of the peptide/HLA-A2 complex. Consistent with this finding,
in peripheral blood from 95 human subjects, we were unable to identify higher
frequencies of T cells specific for either the native or modified peptide. These
data strongly support the conclusion that the greater immunogenicity of the
gp100(209-2M) peptide is due to the enhanced stability of the peptide/MHC
complex, validating the anchor-fixing approach for generating therapeutic
vaccine candidates. Thermodynamic data suggest that the enhanced stability of
the T2M-modified peptide/HLA-A2 complex is attributable to the increased
hydrophobicity of the modified peptide, but the gain due to hydrophobicity is
offset considerably by the loss of a hydrogen bond made by the native peptide to
the HLA-A2 molecule. Our findings have broad implications for the optimization
of current vaccine-design strategies.
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Literature references that cite this PDB file's key reference
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PubMed id
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Reference
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D.K.Cole,
E.S.Edwards,
K.K.Wynn,
M.Clement,
J.J.Miles,
K.Ladell,
J.Ekeruche,
E.Gostick,
K.J.Adams,
A.Skowera,
M.Peakman,
L.Wooldridge,
D.A.Price,
and
A.K.Sewell
(2010).
Modification of MHC anchor residues generates heteroclitic peptides that alter TCR binding and T cell recognition.
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J Immunol,
185,
2600-2610.
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K.R.Jordan,
R.H.McMahan,
C.B.Kemmler,
J.W.Kappler,
and
J.E.Slansky
(2010).
Peptide vaccines prevent tumor growth by activating T cells that respond to native tumor antigens.
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Proc Natl Acad Sci U S A,
107,
4652-4657.
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D.K.Cole,
F.Yuan,
P.J.Rizkallah,
J.J.Miles,
E.Gostick,
D.A.Price,
G.F.Gao,
B.K.Jakobsen,
and
A.K.Sewell
(2009).
Germ line-governed recognition of a cancer epitope by an immunodominant human T-cell receptor.
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J Biol Chem,
284,
27281-27289.
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PDB code:
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K.D.Jensen,
E.E.Sercarz,
and
C.R.Gabaglia
(2009).
Altered peptide ligands can modify the Th2 T cell response to the immunodominant 161-175 peptide of LACK (Leishmania homolog for the receptor of activated C kinase).
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Mol Immunol,
46,
366-374.
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N.A.Bowerman,
L.A.Colf,
K.C.Garcia,
and
D.M.Kranz
(2009).
Different strategies adopted by K(b) and L(d) to generate T cell specificity directed against their respective bound peptides.
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J Biol Chem,
284,
32551-32561.
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N.A.Bowerman,
T.S.Crofts,
L.Chlewicki,
P.Do,
B.M.Baker,
K.Christopher Garcia,
and
D.M.Kranz
(2009).
Engineering the binding properties of the T cell receptor:peptide:MHC ternary complex that governs T cell activity.
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Mol Immunol,
46,
3000-3008.
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O.Y.Borbulevych,
K.H.Piepenbrink,
B.E.Gloor,
D.R.Scott,
R.F.Sommese,
D.K.Cole,
A.K.Sewell,
and
B.M.Baker
(2009).
T cell receptor cross-reactivity directed by antigen-dependent tuning of peptide-MHC molecular flexibility.
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Immunity,
31,
885-896.
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PDB codes:
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V.Pavelic,
M.S.Matter,
S.Mumprecht,
I.Breyer,
and
A.F.Ochsenbein
(2009).
CTL induction by cross-priming is restricted to immunodominant epitopes.
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Eur J Immunol,
39,
704-716.
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P.Johansen,
T.Storni,
L.Rettig,
Z.Qiu,
A.Der-Sarkissian,
K.A.Smith,
V.Manolova,
K.S.Lang,
G.Senti,
B.Müllhaupt,
T.Gerlach,
R.F.Speck,
A.Bot,
and
T.M.Kündig
(2008).
Antigen kinetics determines immune reactivity.
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Proc Natl Acad Sci U S A,
105,
5189-5194.
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O.Y.Borbulevych,
F.K.Insaidoo,
T.K.Baxter,
D.J.Powell,
L.A.Johnson,
N.P.Restifo,
and
B.M.Baker
(2007).
Structures of MART-126/27-35 Peptide/HLA-A2 complexes reveal a remarkable disconnect between antigen structural homology and T cell recognition.
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J Mol Biol,
372,
1123-1136.
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PDB codes:
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J.A.Guevara-Patiño,
M.E.Engelhorn,
M.J.Turk,
C.Liu,
F.Duan,
G.Rizzuto,
A.D.Cohen,
T.Merghoub,
J.D.Wolchok,
and
A.N.Houghton
(2006).
Optimization of a self antigen for presentation of multiple epitopes in cancer immunity.
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J Clin Invest,
116,
1382-1390.
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P.K.Srivastava
(2006).
Therapeutic cancer vaccines.
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Curr Opin Immunol,
18,
201-205.
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S.Viatte,
P.M.Alves,
and
P.Romero
(2006).
Reverse immunology approach for the identification of CD8 T-cell-defined antigens: advantages and hurdles.
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Immunol Cell Biol,
84,
318-330.
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S.A.Rosenberg,
R.M.Sherry,
K.E.Morton,
W.J.Scharfman,
J.C.Yang,
S.L.Topalian,
R.E.Royal,
U.Kammula,
N.P.Restifo,
M.S.Hughes,
D.Schwartzentruber,
D.M.Berman,
S.L.Schwarz,
L.T.Ngo,
S.A.Mavroukakis,
D.E.White,
and
S.M.Steinberg
(2005).
Tumor progression can occur despite the induction of very high levels of self/tumor antigen-specific CD8+ T cells in patients with melanoma.
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J Immunol,
175,
6169-6176.
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The most recent references are shown first.
Citation data come partly from CiteXplore and partly
from an automated harvesting procedure. Note that this is likely to be
only a partial list as not all journals are covered by
either method. However, we are continually building up the citation data
so more and more references will be included with time.
Where a reference describes a PDB structure, the PDB
code is
shown on the right.
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Links
