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* Residue conservation analysis
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DOI no:
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J Mol Biol
267:1207-1222
(1997)
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PubMed id:
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Three-dimensional structure of an Fab-peptide complex: structural basis of HIV-1 protease inhibition by a monoclonal antibody.
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J.Lescar,
R.Stouracova,
M.M.Riottot,
V.Chitarra,
J.Brynda,
M.Fabry,
M.Horejsi,
J.Sedlacek,
G.A.Bentley.
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ABSTRACT
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F11.2.32, a monoclonal antibody raised against HIV-1 protease (Kd = 5 nM), which
inhibits proteolytic activity of the enzyme (K(inh) = 35(+/-3)nM), has been
studied by crystallographic methods. The three-dimensional structure of the
complex between the Fab fragment and a synthetic peptide, spanning residues 36
to 46 of the protease, has been determined at 2.2 A resolution, and that of the
Fab in the free state has been determined at 2.6 A resolution. The refined model
of the complex reveals ten well-ordered residues of the peptide (P36 to P45)
bound in a hydrophobic cavity at the centre of the antigen-binding site. The
peptide adopts a beta hairpin-like structure in which residues P38 to P42 form a
type II beta-turn conformation. An intermolecular antiparallel beta-sheet is
formed between the peptide and the CDR3-H loop of the antibody; additional polar
interactions occur between main-chain atoms of the peptide and hydroxyl groups
from tyrosine residues protruding from CDR1-L and CDR3-H. Three water molecules,
located at the antigen-antibody interface, mediate polar interactions between
the peptide and the most buried hypervariable loops, CDR3-L and CDR1-H. A
comparison between the free and complexed Fab fragments shows that significant
conformational changes occur in the long hypervariable regions, CDR1-L and
CDR3-H, upon binding the peptide. The conformation of the bound peptide, which
shows no overall structural similarity to the corresponding segment in HIV-1
protease, suggests that F11.2.32 might inhibit proteolysis by distorting the
native structure of the enzyme.
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Selected figure(s)
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Figure 5.
Figure 5. View of the interaction between the peptide
and the molecular surface of the antigen-binding site,
colour coded for electrostatic potential: red for negative
and blue for positive; prepared with program GRASP
(Nicholls et al., 1991).
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Figure 7.
Figure 7. Comparison between the structure adopted by peptide(P36-P46) in the complex with Fab F11.2.32 and the
conformation adopted by this segment in the native protease (PDB entry code 3hvp). (a) A schematic view of the pro-
tease in which the location of the epitope recognised by F11.2.32 is shown in red. (b) Ramachandran graph indicating
the differences in f-j angles of the segment 36 to 46 in the bound peptide (black) and the protease (red); residues are
named at the positions for the bound peptide and broken lines connect equivalent residues of the peptide and the
protease. Comparison of residues 36 to 45 of the protease (red) and bound peptide (yellow): (c) after superimposing
residues 36 to 40 and (d) after superimposing residues 41 to 44. The Figure was prepared with program MOLSCRIPT
(Kraulis, 1991).
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The above figures are
reprinted
by permission from Elsevier:
J Mol Biol
(1997,
267,
1207-1222)
copyright 1997.
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Figures were
selected
by an automated process.
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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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N.Krauss,
H.Wessner,
K.Welfle,
H.Welfle,
C.Scholz,
M.Seifert,
K.Zubow,
J.Aÿ,
M.Hahn,
P.Scheerer,
A.Skerra,
and
W.Höhne
(2008).
The structure of the anti-c-myc antibody 9E10 Fab fragment/epitope peptide complex reveals a novel binding mode dominated by the heavy chain hypervariable loops.
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Proteins,
73,
552-565.
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PDB codes:
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J.Brynda,
P.Rezácová,
M.Fábry,
M.Horejsí,
R.Stouracová,
M.Soucek,
M.Hradílek,
J.Konvalinka,
and
J.Sedlácek
(2004).
Inhibitor binding at the protein interface in crystals of a HIV-1 protease complex.
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Acta Crystallogr D Biol Crystallogr,
60,
1943-1948.
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PDB code:
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R.Núñez Miguel,
J.Sanders,
J.Jeffreys,
H.Depraetere,
M.Evans,
T.Richards,
T.L.Blundell,
B.Rees Smith,
and
J.Furmaniak
(2004).
Analysis of the thyrotropin receptor-thyrotropin interaction by comparative modeling.
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Thyroid,
14,
991.
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F.E.Romesberg
(2003).
Multidisciplinary experimental approaches to characterizing biomolecular dynamics.
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Chembiochem,
4,
563-571.
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J.Lescar,
J.Brynda,
M.Fabry,
M.Horejsi,
P.Rezacova,
J.Sedlacek,
and
G.A.Bentley
(2003).
Structure of a single-chain Fv fragment of an antibody that inhibits the HIV-1 and HIV-2 proteases.
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Acta Crystallogr D Biol Crystallogr,
59,
955-957.
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PDB code:
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S.Fuchs,
R.Kasher,
M.Balass,
T.Scherf,
M.Harel,
M.Fridkin,
J.L.Sussman,
and
E.Katchalski-Katzir
(2003).
The binding site of acetylcholine receptor: from synthetic peptides to solution and crystal structure.
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Ann N Y Acad Sci,
998,
93.
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D.Altschuh
(2002).
Cyclosporin A as a model antigen: immunochemical and structural studies.
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J Mol Recognit,
15,
277-285.
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P.Rezacova,
J.Brynda,
M.Fabry,
M.Horejsi,
R.Stouracova,
J.Lescar,
V.Chitarra,
M.M.Riottot,
J.Sedlacek,
and
G.A.Bentley
(2002).
Inhibition of HIV protease by monoclonal antibodies.
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J Mol Recognit,
15,
272-276.
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T.Scherf,
R.Kasher,
M.Balass,
M.Fridkin,
S.Fuchs,
and
E.Katchalski-Katzir
(2001).
A beta -hairpin structure in a 13-mer peptide that binds alpha -bungarotoxin with high affinity and neutralizes its toxicity.
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Proc Natl Acad Sci U S A,
98,
6629-6634.
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PDB codes:
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A.P.Campbell,
W.Y.Wong,
R.T.Irvin,
and
B.D.Sykes
(2000).
Interaction of a bacterially expressed peptide from the receptor binding domain of Pseudomonas aeruginosa pili strain PAK with a cross-reactive antibody: conformation of the bound peptide.
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Biochemistry,
39,
14847-14864.
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P.B.Furtado,
R.Furmonaviciene,
J.McElveen,
H.F.Sewell,
and
F.Shakib
(2000).
Prediction of the interacting surfaces in a trimolecular complex formed between the major dust mite allergen Der p 1, a mouse monoclonal anti-Der p 1 antibody, and its anti-idiotype.
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Mol Pathol,
53,
324-332.
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J.L.Pellequer,
S.Chen,
V.A.Roberts,
J.A.Tainer,
and
E.D.Getzoff
(1999).
Unraveling the effect of changes in conformation and compactness at the antibody V(L)-V(H) interface upon antigen binding.
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J Mol Recognit,
12,
267-275.
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J.Lescar,
J.Brynda,
P.Rezacova,
R.Stouracova,
M.M.Riottot,
V.Chitarra,
M.Fabry,
M.Horejsi,
J.Sedlacek,
and
G.A.Bentley
(1999).
Inhibition of the HIV-1 and HIV-2 proteases by a monoclonal antibody.
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Protein Sci,
8,
2686-2696.
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PDB code:
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L.Choulier,
N.Rauffer-Bruyère,
M.Ben Khalifa,
F.Martin,
T.Vernet,
and
D.Altschuh
(1999).
Kinetic analysis of the effect on Fab binding of identical substitutions in a peptide and its parent protein.
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Biochemistry,
38,
3530-3537.
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P.Rondard,
and
H.Bedouelle
(1998).
A mutational approach shows similar mechanisms of recognition for the isolated and integrated versions of a protein epitope.
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J Biol Chem,
273,
34753-34759.
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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
codes are
shown on the right.
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Links
