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* Residue conservation analysis
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Nature
365:859-863
(1993)
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PubMed id:
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Molecular basis of crossreactivity and the limits of antibody-antigen complementarity.
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J.H.Arevalo,
M.J.Taussig,
I.A.Wilson.
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ABSTRACT
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Two major unanswered questions concerning the specificity of antibodies are: how
do structurally different antigens bind with high affinity to the same antibody,
and what are the limits of the antibody combining site complementarity and
flexibility that contribute to such crossreactivity? We report here a
comparative analysis of the X-ray structures of five conformationally different
steroids in complex with the Fab' fragment of an anti-progesterone antibody DB3
at 2.7 A. This antibody is unable to complement completely the shape of the
hydrophobic antigen so that crossreactivity occurs with other ligands without
major structural rearrangements of the binding site. Antigen specificity can be
explained through conserved interactions of DB3 with the steroid D-ring, whereas
some of the crossreactivity is realized through different binding orientations
of the steroid skeleton that place the A-ring into alternative pockets on the
antibody surface. The restricted gene usage of the VGAM3.8 family in the
generation of anti-progesterone monoclonal antibodies may be explained by the
specific interaction of VH hallmark residues with the steroid D-ring. This first
detailed structure of steroid interactions with a protein could be applied to
the understanding of general mechanisms of steroid recognition as well as in the
design of specific binding sites for small hydrophobic ligands.
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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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I.Nobeli,
A.D.Favia,
and
J.M.Thornton
(2009).
Protein promiscuity and its implications for biotechnology.
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Nat Biotechnol,
27,
157-167.
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M.Ui,
Y.Tanaka,
T.Tsumuraya,
I.Fujii,
M.Inoue,
M.Hirama,
and
K.Tsumoto
(2008).
How protein recognizes ladder-like polycyclic ethers. Interactions between ciguatoxin (CTX3C) fragments and its specific antibody 10C9.
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J Biol Chem,
283,
19440-19447.
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PDB codes:
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P.Verdino,
C.Aldag,
D.Hilvert,
and
I.A.Wilson
(2008).
Closely related antibody receptors exploit fundamentally different strategies for steroid recognition.
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Proc Natl Acad Sci U S A,
105,
11725-11730.
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PDB codes:
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R.Das,
and
D.Baker
(2008).
Macromolecular modeling with rosetta.
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Annu Rev Biochem,
77,
363-382.
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T.Young,
R.Abel,
B.Kim,
B.J.Berne,
and
R.A.Friesner
(2007).
Motifs for molecular recognition exploiting hydrophobic enclosure in protein-ligand binding.
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Proc Natl Acad Sci U S A,
104,
808-813.
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M.He,
M.Hamon,
H.Liu,
A.L.Corper,
and
M.J.Taussig
(2006).
Effects of mutation at the D-JH junction on affinity, specificity, and idiotypy of anti-progesterone antibody DB3.
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Protein Sci,
15,
2141-2148.
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N.M.Grubor,
D.W.Armstrong,
and
R.Jankowiak
(2006).
Flow-through partial-filling affinity capillary electrophoresis using a crossreactive antibody for enantiomeric separations.
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Electrophoresis,
27,
1078-1083.
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N.M.Grubor,
J.Hayes,
G.J.Small,
and
R.Jankowiak
(2005).
Cross-reactivity and conformational multiplicity of an anti-polycyclic aromatic hydrocarbon mAb.
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Proc Natl Acad Sci U S A,
102,
7453-7458.
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A.Piatesi,
and
D.Hilvert
(2004).
Immunological optimization of a generic hydrophobic pocket for high affinity hapten binding and Diels-Alder activity.
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Chembiochem,
5,
460-466.
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M.Geva,
M.Eisenstein,
and
L.Addadi
(2004).
Antibody recognition of chiral surfaces. Structural models of antibody complexes with leucine-leucine-tyrosine crystal surfaces.
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Proteins,
55,
862-873.
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T.Laitinen,
J.A.Kankare,
and
M.Peräkylä
(2004).
Free energy simulations and MM-PBSA analyses on the affinity and specificity of steroid binding to antiestradiol antibody.
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Proteins,
55,
34-43.
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N.Nordman,
J.Valjakka,
and
M.Peräkylä
(2003).
Analysis of the binding energies of testosterone, 5alpha-dihydrotestosterone, androstenedione and dehydroepiandrosterone sulfate with an antitestosterone antibody.
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Proteins,
50,
135-143.
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E.Yuriev,
and
P.A.Ramsland
(2002).
Mcg light chain dimer as a model system for ligand design: a docking study.
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J Mol Recognit,
15,
331-340.
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J.Valjakka,
K.Takkinenz,
T.Teerinen,
H.Söderlund,
and
J.Rouvinen
(2002).
Structural insights into steroid hormone binding: the crystal structure of a recombinant anti-testosterone Fab fragment in free and testosterone-bound forms.
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J Biol Chem,
277,
4183-4190.
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PDB codes:
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D.J.Tantillo,
and
K.N.Houk
(2001).
Canonical binding arrays as molecular recognition elements in the immune system: tetrahedral anions and the ester hydrolysis transition state.
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Chem Biol,
8,
535-545.
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D.Jain,
K.J.Kaur,
and
D.M.Salunke
(2001).
Plasticity in protein-peptide recognition: crystal structures of two different peptides bound to concanavalin A.
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Biophys J,
80,
2912-2921.
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PDB codes:
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E.Yuriev,
P.A.Ramsland,
and
A.B.Edmundson
(2001).
Docking of combinatorial peptide libraries into a broadly cross-reactive human IgM.
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J Mol Recognit,
14,
172-184.
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F.Bettsworth,
C.Monnet,
B.Watelet,
N.Battail-Poirot,
B.Gilquin,
M.Jolivet,
A.Menez,
M.Arnaud,
and
F.Ducancel
(2001).
Functional characterization of two anti-estradiol antibodies as deduced from modelling and site-directed mutagenesis experiments.
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J Mol Recognit,
14,
99.
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P.V.Afonin,
A.V.Fokin,
I.N.Tsygannik,
I.Y.Mikhailova,
L.V.Onoprienko,
I.I.Mikhaleva,
V.T.Ivanov,
T.Y.Mareeva,
V.A.Nesmeyanov,
N.Li,
W.A.Pangborn,
W.L.Duax,
and
V.Z.Pletnev
(2001).
Crystal structure of an anti-interleukin-2 monoclonal antibody Fab complexed with an antigenic nonapeptide.
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Protein Sci,
10,
1514-1521.
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PDB code:
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D.Hilvert
(2000).
Critical analysis of antibody catalysis.
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Annu Rev Biochem,
69,
751-793.
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J.Chen,
Q.Deng,
R.Wang,
K.Houk,
and
D.Hilvert
(2000).
Shape complementarity, binding-site dynamics, and transition state stabilization: a theoretical study of Diels-Alder catalysis by antibody 1E9.
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Chembiochem,
1,
255-261.
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R.D.Kirsch,
D.Beale,
M.He,
A.L.Corper,
U.Krawinkel-Brenig,
and
M.J.Taussig
(2000).
Anti-anti-idiotypic (Ab3) antibodies that bind progesterone-11alpha-bovine serum albumin differ in their combining sites from antibodies raised directly against the antigen.
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Immunology,
100,
152-164.
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U.Lamminmäki,
and
J.Kankare
(2000).
Crystallization and preliminary X-ray analysis of a recombinant Fab fragment in complex with 17beta-oestradiol.
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Acta Crystallogr D Biol Crystallogr,
56,
1670-1672.
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Y.Nishimiya,
K.Tsumoto,
M.Shiroishi,
K.Yutani,
and
I.Kumagai
(2000).
Thermodynamic consequences of grafting enhanced affinity toward the mutated antigen onto an antibody. The case of anti-lysozyme antibody, HyHEL-10.
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J Biol Chem,
275,
12813-12820.
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C.A.Sotriffer,
W.Flader,
A.Cooper,
B.M.Rode,
D.S.Linthicum,
K.R.Liedl,
and
J.M.Varga
(1999).
Ligand binding by antibody IgE Lb4: assessment of binding site preferences using microcalorimetry, docking, and free energy simulations.
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Biophys J,
76,
2966-2977.
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J.Xu,
Q.Deng,
J.Chen,
K.N.Houk,
J.Bartek,
D.Hilvert,
and
I.A.Wilson
(1999).
Evolution of shape complementarity and catalytic efficiency from a primordial antibody template.
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Science,
286,
2345-2348.
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PDB code:
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F.E.Romesberg,
B.Spiller,
P.G.Schultz,
and
R.C.Stevens
(1998).
Immunological origins of binding and catalysis in a Diels-Alderase antibody.
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Science,
279,
1929-1933.
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PDB codes:
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P.Chames,
and
D.Baty
(1998).
Engineering of an anti-steroid antibody: amino acid substitutions change antibody fine specificity from cortisol to estradiol.
|
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Clin Chem Lab Med,
36,
355-359.
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S.Riva,
M.Mendozza,
G.Carrea,
P.Chattopadhyay,
and
A.Tramontano
(1998).
Comparison of antibody and albumin catalyzed hydrolysis of steroidal p-nitrophenylcarbonates.
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Appl Biochem Biotechnol,
75,
33-44.
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A.Kramer,
T.Keitel,
K.Winkler,
W.Stöcklein,
W.Höhne,
and
J.Schneider-Mergener
(1997).
Molecular basis for the binding promiscuity of an anti-p24 (HIV-1) monoclonal antibody.
|
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Cell,
91,
799-809.
|
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T.Keitel,
A.Kramer,
H.Wessner,
C.Scholz,
J.Schneider-Mergener,
and
W.Höhne
(1997).
Crystallographic analysis of anti-p24 (HIV-1) monoclonal antibody cross-reactivity and polyspecificity.
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Cell,
91,
811-820.
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PDB codes:
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C.A.Sotriffer,
R.H.Winger,
K.R.Liedl,
B.M.Rode,
and
J.M.Varga
(1996).
Comparative docking studies on ligand binding to the multispecific antibodies IgE-La2 and IgE-Lb4.
|
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J Comput Aided Mol Des,
10,
305-320.
|
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D.Higginson-Clarke,
R.Guevara García,
C.Rodríguez Tanty,
A.López Brauet,
L.López-Canovas,
A.M.Riverón Rojas,
and
A.Macías Cabrera
(1996).
Monoclonal antibody affinities of structurally related modified nucleosides.
|
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Mol Chem Neuropathol,
28,
269-277.
|
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F.Brard,
F.Jovelin,
S.Petit,
F.Tron,
and
D.Gilbert
(1996).
Structural properties and mutation patterns of anti-nucleosome monoclonal antibodies are similar to those of anti-DNA antibodies.
|
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Eur J Immunol,
26,
1587-1594.
|
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L.C.Hsieh-Wilson,
P.G.Schultz,
and
R.C.Stevens
(1996).
Insights into antibody catalysis: structure of an oxygenation catalyst at 1.9-angstrom resolution.
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Proc Natl Acad Sci U S A,
93,
5363-5367.
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PDB codes:
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R.H.Winger,
K.R.Liedl,
C.A.Sotriffer,
A.M.Gamper,
B.M.Rode,
R.T.Kroemer,
and
J.M.Varga
(1996).
Prediction of IgE(Lb4)-ligand complex structures by automated docking.
|
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J Mol Recognit,
9,
239-246.
|
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T.I.Oprea,
and
A.E.García
(1996).
Three-dimensional quantitative structure-activity relationships of steroid aromatase inhibitors.
|
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J Comput Aided Mol Des,
10,
186-200.
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M.Shoham,
T.Scherf,
J.Anglister,
M.Levitt,
E.A.Merritt,
and
W.G.Hol
(1995).
Structural diversity in a conserved cholera toxin epitope involved in ganglioside binding.
|
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Protein Sci,
4,
841-848.
|
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P.M.Tang,
L.A.Foltz,
W.C.Mahoney,
and
P.A.Schueler
(1995).
A high affinity digoxin-binding protein displayed on M13 is functionally identical to the native protein.
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J Biol Chem,
270,
7829-7835.
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S.D.Miklasz,
G.A.Gulliver,
and
E.W.Voss
(1995).
High-affinity rat anti-fluorescein monoclonal antibody with unique fine specificity properties including differential recognition of dynamic ligand analogues.
|
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J Mol Recognit,
8,
258-269.
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I.A.Wilson,
and
R.L.Stanfield
(1994).
Antibody-antigen interactions: new structures and new conformational changes.
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Curr Opin Struct Biol,
4,
857-867.
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R.L.Malby,
W.R.Tulip,
V.R.Harley,
J.L.McKimm-Breschkin,
W.G.Laver,
R.G.Webster,
and
P.M.Colman
(1994).
The structure of a complex between the NC10 antibody and influenza virus neuraminidase and comparison with the overlapping binding site of the NC41 antibody.
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Structure,
2,
733-746.
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PDB code:
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R.L.Stanfield,
and
I.A.Wilson
(1994).
Antigen-induced conformational changes in antibodies: a problem for structural prediction and design.
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Trends Biotechnol,
12,
275-279.
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U.Christen,
J.Quinn,
S.J.Yeaman,
J.G.Kenna,
J.B.Clarke,
A.J.Gandolfi,
and
J.Gut
(1994).
Identification of the dihydrolipoamide acetyltransferase subunit of the human pyruvate dehydrogenase complex as an autoantigen in halothane hepatitis. Molecular mimicry of trifluoroacetyl-lysine by lipoic acid.
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Eur J Biochem,
223,
1035-1047.
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R.L.Stanfield,
M.Takimoto-Kamimura,
J.M.Rini,
A.T.Profy,
and
I.A.Wilson
(1993).
Major antigen-induced domain rearrangements in an antibody.
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Structure,
1,
83-93.
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PDB codes:
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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
