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DOI no:
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J Med Chem
43:2135-2148
(2000)
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PubMed id:
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Peptide and peptide mimetic inhibitors of antigen presentation by HLA-DR class II MHC molecules. Design, structure-activity relationships, and X-ray crystal structures.
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D.R.Bolin,
A.L.Swain,
R.Sarabu,
S.J.Berthel,
P.Gillespie,
N.J.Huby,
R.Makofske,
L.Orzechowski,
A.Perrotta,
K.Toth,
J.P.Cooper,
N.Jiang,
F.Falcioni,
R.Campbell,
D.Cox,
D.Gaizband,
C.J.Belunis,
D.Vidovic,
K.Ito,
R.Crowther,
U.Kammlott,
X.Zhang,
R.Palermo,
D.Weber,
J.Guenot,
Z.Nagy,
G.L.Olson.
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ABSTRACT
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Molecular features of ligand binding to MHC class II HLA-DR molecules have been
elucidated through a combination of peptide structure-activity studies and
structure-based drug design, resulting in analogues with nanomolar affinity in
binding assays. Stabilization of lead compounds against cathepsin B cleavage by
N-methylation of noncritical backbone NH groups or by dipeptide mimetic
substitutions has generated analogues that compete effectively against protein
antigens in cellular assays, resulting in inhibition of T-cell proliferation.
Crystal structures of four ternary complexes of different peptide mimetics with
the rheumatoid arthritis-linked MHC DRB10401 and the bacterial superantigen SEB
have been obtained. Peptide-sugar hybrids have also been identified using a
structure-based design approach in which the sugar residue replaces a dipeptide.
These studies illustrate the complementary roles played by phage display library
methods, peptide analogue SAR, peptide mimetics substitutions, and
structure-based drug design in the discovery of inhibitors of antigen
presentation by MHC class II HLA-DR molecules.
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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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C.A.Painter,
A.Cruz,
G.E.López,
L.J.Stern,
and
Z.Zavala-Ruiz
(2008).
Model for the peptide-free conformation of class II MHC proteins.
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PLoS ONE, 3,
e2403.
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J.M.Fletcher,
C.J.Morton,
R.A.Zwar,
S.S.Murray,
P.D.O'Leary,
and
R.A.Hughes
(2008).
Design of a Conformationally Defined and Proteolytically Stable Circular Mimetic of Brain-derived Neurotrophic Factor.
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J Biol Chem, 283,
33375-33383.
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J.Cluzeau,
and
W.D.Lubell
(2005).
Design, synthesis, and application of azabicyclo[X.Y.0]alkanone amino acids as constrained dipeptide surrogates and peptide mimics.
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Biopolymers, 80,
98.
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G.J.Carven,
S.Chitta,
I.Hilgert,
M.M.Rushe,
R.F.Baggio,
M.Palmer,
J.E.Arenas,
J.L.Strominger,
V.Horejsi,
L.Santambrogio,
and
L.J.Stern
(2004).
Monoclonal antibodies specific for the empty conformation of HLA-DR1 reveal aspects of the conformational change associated with peptide binding.
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J Biol Chem, 279,
16561-16570.
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H.D.Schafroth,
and
C.A.Floudas
(2004).
Predicting peptide binding to MHC pockets via molecular modeling, implicit solvation, and global optimization.
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Proteins, 54,
534-556.
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Z.Zavala-Ruiz,
E.J.Sundberg,
J.D.Stone,
D.B.DeOliveira,
I.C.Chan,
J.Svendsen,
R.A.Mariuzza,
and
L.J.Stern
(2003).
Exploration of the P6/P7 region of the peptide-binding site of the human class II major histocompatability complex protein HLA-DR1.
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J Biol Chem, 278,
44904-44912.
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PDB code:
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B.J.McFarland,
and
C.Beeson
(2002).
Binding interactions between peptides and proteins of the class II major histocompatibility complex.
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Med Res Rev, 22,
168-203.
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B.J.McFarland,
J.F.Katz,
C.Beeson,
and
A.J.Sant
(2001).
Energetic asymmetry among hydrogen bonds in MHC class II*peptide complexes.
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Proc Natl Acad Sci U S A, 98,
9231-9236.
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H.Beck,
G.Schwarz,
C.J.Schröter,
M.Deeg,
D.Baier,
S.Stevanovic,
E.Weber,
C.Driessen,
and
H.Kalbacher
(2001).
Cathepsin S and an asparagine-specific endoprotease dominate the proteolytic processing of human myelin basic protein in vitro.
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Eur J Immunol, 31,
3726-3736.
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H.Noguchi,
T.Hanai,
H.Honda,
L.C.Harrison,
and
T.Kobayashi
(2001).
Fuzzy neural network-based prediction of the motif for MHC class II binding peptides.
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J Biosci Bioeng, 92,
227-231.
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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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178 a.a.
181 a.a.
226 a.a.
