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* Residue conservation analysis
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J Mol Biol
229:969-995
(1993)
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PubMed id:
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X-ray structures of the antigen-binding domains from three variants of humanized anti-p185HER2 antibody 4D5 and comparison with molecular modeling.
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C.Eigenbrot,
M.Randal,
L.Presta,
P.Carter,
A.A.Kossiakoff.
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ABSTRACT
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The X-ray structures of 1 Fv and 2 Fab humanized anti-p185HER2 antibody
fragments (IgG1-kappa) have been determined at a resolution between 2.7 A and
2.2 A. The antibodies are three different versions of a human antibody framework
onto which the antigen recognition loops from a murine antibody (4D5) have been
grafted. The sequences of the three versions differ in the framework region at
positions L55, H78 and H102. The version 8 Fv fragment crystallizes in space
group P2(1) with cell parameters a = 37.6 A, b = 63.4 A, c = 90.2 A, beta = 98.2
degrees, with two molecules per asymmetric unit, and has been refined against
data 10.0 A-2.2 A to an R-factor of 18.3%. Versions 4 and 7 Fabs crystallize in
space group P1 with cell parameters a = 39.2 A, b = 80.2 A, c = 86.1 A, alpha =
113.1 degrees, beta = 92.7 A, gamma = 102.6 A and two molecules per asymmetric
unit. Version 4 has been refined against data 10.0 A-2.5 A resolution to an
R-factor of 17.9%. Version 7 has been refined against data 10 A-2.7 A to an
R-factor of 17.1%. The X-ray structures have been used to assess the accuracy of
structural predictions made via molecular modeling, and they confirm the
structural role of certain framework residues and the conformations of five of
six complementarity determining regions (CDRS). The average deviation of the
model from the X-ray structures is within the range observed among the X-ray
structures for 81% of the C alpha atoms. Of the hydrogen bonds common to the
X-ray structures, 94% of the main-chain-main-chain and 79% of the
main-chain-side-chain ones were predicted by the model. The side-chain
conformation was predicted correctly for 79% of the buried residues. The third
CDR in the heavy chain is variable, differing by up to 8 A between molecules
within an asymmetric unit. The structural relationship between variable domains
of light and heavy chains is not significantly altered by the absence of
constant domains in the Fv molecule. The antigen-binding potential of an unusual
light chain sequence has been confirmed. The arginine at position 66 interacts
with the first light chain CDR, but in a fashion somewhat different than
predicted. A substitution of a leucine for an alanine side-chain directed
between the beta-sheets has only relatively small and local effects.(ABSTRACT
TRUNCATED AT 400 WORDS)
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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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|
|
|
Y.Koldobskaya,
E.M.Duguid,
D.M.Shechner,
N.B.Suslov,
J.Ye,
S.S.Sidhu,
D.P.Bartel,
S.Koide,
A.A.Kossiakoff,
and
J.A.Piccirilli
(2011).
A portable RNA sequence whose recognition by a synthetic antibody facilitates structural determination.
|
| |
Nat Struct Mol Biol,
18,
100-106.
|
|
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|
|
|
|
H.D.Brightbill,
S.Jeet,
Z.Lin,
D.Yan,
M.Zhou,
M.Tan,
A.Nguyen,
S.Yeh,
D.Delarosa,
S.R.Leong,
T.Wong,
Y.Chen,
M.Ultsch,
E.Luis,
S.R.Ramani,
J.Jackman,
L.Gonzalez,
M.S.Dennis,
A.Chuntharapai,
L.DeForge,
Y.G.Meng,
M.Xu,
C.Eigenbrot,
W.P.Lee,
C.J.Refino,
M.Balazs,
and
L.C.Wu
(2010).
Antibodies specific for a segment of human membrane IgE deplete IgE-producing B cells in humanized mice.
|
| |
J Clin Invest,
120,
2218-2229.
|
|
|
PDB code:
|
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|
|
|
|
|
|
Y.Wu,
C.Cain-Hom,
L.Choy,
T.J.Hagenbeek,
G.P.de Leon,
Y.Chen,
D.Finkle,
R.Venook,
X.Wu,
J.Ridgway,
D.Schahin-Reed,
G.J.Dow,
A.Shelton,
S.Stawicki,
R.J.Watts,
J.Zhang,
R.Choy,
P.Howard,
L.Kadyk,
M.Yan,
J.Zha,
C.A.Callahan,
S.G.Hymowitz,
and
C.W.Siebel
(2010).
Therapeutic antibody targeting of individual Notch receptors.
|
| |
Nature,
464,
1052-1057.
|
|
|
PDB code:
|
|
|
|
|
|
|
|
A.Honegger,
A.D.Malebranche,
D.Röthlisberger,
and
A.Plückthun
(2009).
The influence of the framework core residues on the biophysical properties of immunoglobulin heavy chain variable domains.
|
| |
Protein Eng Des Sel,
22,
121-134.
|
|
|
|
|
|
|
M.Kügler,
C.Stein,
M.Schwenkert,
D.Saul,
L.Vockentanz,
T.Huber,
S.K.Wetzel,
O.Scholz,
A.Plückthun,
A.Honegger,
and
G.H.Fey
(2009).
Stabilization and humanization of a single-chain Fv antibody fragment specific for human lymphocyte antigen CD19 by designed point mutations and CDR-grafting onto a human framework.
|
| |
Protein Eng Des Sel,
22,
135-147.
|
|
|
|
|
|
|
M.Schlapschy,
M.Fogarasi,
H.Gruber,
O.Gresch,
C.Schäfer,
Y.Aguib,
and
A.Skerra
(2009).
Functional humanization of an anti-CD16 Fab fragment: obstacles of switching from murine {lambda} to human {lambda} or {kappa} light chains.
|
| |
Protein Eng Des Sel,
22,
175-188.
|
|
|
|
|
|
|
J.D.Ye,
V.Tereshko,
J.K.Frederiksen,
A.Koide,
F.A.Fellouse,
S.S.Sidhu,
S.Koide,
A.A.Kossiakoff,
and
J.A.Piccirilli
(2008).
Synthetic antibodies for specific recognition and crystallization of structured RNA.
|
| |
Proc Natl Acad Sci U S A,
105,
82-87.
|
|
|
PDB code:
|
|
|
|
|
|
|
|
P.A.Barthelemy,
H.Raab,
B.A.Appleton,
C.J.Bond,
P.Wu,
C.Wiesmann,
and
S.S.Sidhu
(2008).
Comprehensive Analysis of the Factors Contributing to the Stability and Solubility of Autonomous Human VH Domains.
|
| |
J Biol Chem,
283,
3639-3654.
|
|
|
PDB code:
|
|
|
|
|
|
|
|
S.H.Jiang,
J.F.Wang,
R.Xu,
Y.J.Liu,
X.N.Wang,
J.Cao,
P.Zhao,
Y.J.Shen,
T.Yang,
H.Yang,
J.A.Jia,
Q.L.Chen,
and
W.Pan
(2008).
Alternate arrangement of PpL B3 domain and SpA D domain creates synergistic double-site binding to VH3 and Vkappa regions of fab.
|
| |
DNA Cell Biol,
27,
423-431.
|
|
|
|
|
|
|
G.Fuh
(2007).
Synthetic antibodies as therapeutics.
|
| |
Expert Opin Biol Ther,
7,
73-87.
|
|
|
|
|
|
|
T.Olafsen,
Z.Gu,
M.A.Sherman,
J.V.Leyton,
M.E.Witkosky,
J.E.Shively,
A.A.Raubitschek,
S.L.Morrison,
A.M.Wu,
and
R.E.Reiter
(2007).
Targeting, imaging, and therapy using a humanized antiprostate stem cell antigen (PSCA) antibody.
|
| |
J Immunother (1997),
30,
396-405.
|
|
|
|
|
|
|
C.W.Adams,
D.E.Allison,
K.Flagella,
L.Presta,
J.Clarke,
N.Dybdal,
K.McKeever,
and
M.X.Sliwkowski
(2006).
Humanization of a recombinant monoclonal antibody to produce a therapeutic HER dimerization inhibitor, pertuzumab.
|
| |
Cancer Immunol Immunother,
55,
717-727.
|
|
|
|
|
|
|
G.Fuh,
P.Wu,
W.C.Liang,
M.Ultsch,
C.V.Lee,
B.Moffat,
and
C.Wiesmann
(2006).
Structure-function studies of two synthetic anti-vascular endothelial growth factor Fabs and comparison with the Avastin Fab.
|
| |
J Biol Chem,
281,
6625-6631.
|
|
|
PDB codes:
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S.M.Deyev,
O.A.Stremovskiy,
S.V.Lukash,
D.V.Karpenko,
O.L.Polyanovsky,
and
R.V.Petrov
(2006).
Production of recombinant antitumor antibodies by HEK-293 cells.
|
| |
Dokl Biochem Biophys,
406,
44-46.
|
|
|
|
|
|
|
A.Honegger,
S.Spinelli,
C.Cambillau,
and
A.Plückthun
(2005).
A mutation designed to alter crystal packing permits structural analysis of a tight-binding fluorescein-scFv complex.
|
| |
Protein Sci,
14,
2537-2549.
|
|
|
PDB codes:
|
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J.S.Marvin,
and
Z.Zhu
(2005).
Recombinant approaches to IgG-like bispecific antibodies.
|
| |
Acta Pharmacol Sin,
26,
649-658.
|
|
|
|
|
|
|
T.Zhou,
D.H.Hamer,
W.A.Hendrickson,
Q.J.Sattentau,
and
P.D.Kwong
(2005).
Interfacial metal and antibody recognition.
|
| |
Proc Natl Acad Sci U S A,
102,
14575-14580.
|
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PDB codes:
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|
|
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E.Carredano,
H.Baumann,
A.Grönberg,
N.Norrman,
G.Glad,
J.Zou,
O.Ersoy,
E.Steensma,
and
A.Axén
(2004).
A novel and conserved pocket of human kappa-Fab fragments: design, synthesis, and verification of directed affinity ligands.
|
| |
Protein Sci,
13,
1476-1488.
|
|
|
|
|
|
|
F.A.Fellouse,
C.Wiesmann,
and
S.S.Sidhu
(2004).
Synthetic antibodies from a four-amino-acid code: a dominant role for tyrosine in antigen recognition.
|
| |
Proc Natl Acad Sci U S A,
101,
12467-12472.
|
|
|
PDB codes:
|
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|
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M.C.Franklin,
K.D.Carey,
F.F.Vajdos,
D.J.Leahy,
A.M.de Vos,
and
M.X.Sliwkowski
(2004).
Insights into ErbB signaling from the structure of the ErbB2-pertuzumab complex.
|
| |
Cancer Cell,
5,
317-328.
|
|
|
PDB code:
|
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|
|
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|
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G.B.Chavali,
A.C.Papageorgiou,
K.A.Olson,
J.W.Fett,
G.Hu,
R.Shapiro,
and
K.R.Acharya
(2003).
The crystal structure of human angiogenin in complex with an antitumor neutralizing antibody.
|
| |
Structure,
11,
875-885.
|
|
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PDB code:
|
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|
|
|
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L.O.Essen,
A.Harrenga,
C.Ostermeier,
and
H.Michel
(2003).
1.3 A X-ray structure of an antibody Fv fragment used for induced membrane-protein crystallization.
|
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Acta Crystallogr D Biol Crystallogr,
59,
677-687.
|
|
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PDB code:
|
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I.Pedroso,
M.P.Irún,
C.Machicado,
and
J.Sancho
(2002).
Four-state equilibrium unfolding of an scFv antibody fragment.
|
| |
Biochemistry,
41,
9873-9884.
|
|
|
|
|
|
|
C.T.Morita,
H.Li,
J.G.Lamphear,
R.R.Rich,
J.D.Fraser,
R.A.Mariuzza,
and
H.K.Lee
(2001).
Superantigen recognition by gammadelta T cells: SEA recognition site for human Vgamma2 T cell receptors.
|
| |
Immunity,
14,
331-344.
|
|
|
|
|
|
|
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.
|
| |
J Mol Recognit,
14,
99.
|
|
|
|
|
|
|
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.
|
| |
Mol Pathol,
53,
324-332.
|
|
|
|
|
|
|
M.A.Starovasnik,
M.P.O'Connell,
W.J.Fairbrother,
and
R.F.Kelley
(1999).
Antibody variable region binding by Staphylococcal protein A: thermodynamic analysis and location of the Fv binding site on E-domain.
|
| |
Protein Sci,
8,
1423-1431.
|
|
|
|
|
|
|
N.Kessler,
D.Perl-Treves,
L.Addadi,
and
M.Eisenstein
(1999).
Structural and chemical complementarity between antibodies and the crystal surfaces they recognize.
|
| |
Proteins,
34,
383-394.
|
|
|
|
|
|
|
S.Odani,
Y.Komori,
and
F.Gejyo
(1999).
Structural analysis of the amyloidogenic kappa Bence Jones protein (FUR).
|
| |
Amyloid,
6,
77-88.
|
|
|
|
|
|
|
Z.C.Fan,
L.Shan,
B.Z.Goldsteen,
L.W.Guddat,
A.Thakur,
N.F.Landolfi,
M.S.Co,
M.Vasquez,
C.Queen,
P.A.Ramsland,
and
A.B.Edmundson
(1999).
Comparison of the three-dimensional structures of a humanized and a chimeric Fab of an anti-gamma-interferon antibody.
|
| |
J Mol Recognit,
12,
19-32.
|
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|
PDB codes:
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H.R.Hoogenboom,
P.Henderikx,
and
de Haard H
(1998).
Creating and engineering human antibodies for immunotherapy.
|
| |
Adv Drug Deliv Rev,
31,
5.
|
|
|
|
|
|
|
Y.A.Muller,
Y.Chen,
H.W.Christinger,
B.Li,
B.C.Cunningham,
H.B.Lowman,
and
A.M.de Vos
(1998).
VEGF and the Fab fragment of a humanized neutralizing antibody: crystal structure of the complex at 2.4 A resolution and mutational analysis of the interface.
|
| |
Structure,
6,
1153-1167.
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PDB code:
|
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|
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|
|
|
A.A.Komissarov,
M.T.Marchbank,
M.J.Calcutt,
T.P.Quinn,
and
S.L.Deutscher
(1997).
Site-specific mutagenesis of a recombinant anti-single-stranded DNA Fab. Role of heavy chain complementarity-determining region 3 residues in antigen interaction.
|
| |
J Biol Chem,
272,
26864-26870.
|
|
|
|
|
|
|
D.Gilbert,
P.Courville,
F.Brard,
P.Joly,
S.Petit,
E.Bernardi,
A.R.Schoofs,
P.Lauret,
and
F.Tron
(1997).
A complementarity-determining region peptide of an anti-desmosome autoantibody may interact with the desmosomal plaque through molecular mimicry with a cytoplasmic desmoglein 1 sequence.
|
| |
Eur J Immunol,
27,
1055-1060.
|
|
|
|
|
|
|
Z.Zhu,
L.G.Presta,
G.Zapata,
and
P.Carter
(1997).
Remodeling domain interfaces to enhance heterodimer formation.
|
| |
Protein Sci,
6,
781-788.
|
|
|
|
|
|
|
C.Tenette,
F.Ducancel,
and
J.C.Smith
(1996).
Structural model of the anti-snake-toxin antibody, M alpha 2,3.
|
| |
Proteins,
26,
9.
|
|
|
|
|
|
|
O.Pritsch,
G.Hudry-Clergeon,
M.Buckle,
Y.Petillot,
J.P.Bouvet,
J.Gagnon,
and
G.Dighiero
(1996).
Can immunoglobulin C(H)1 constant region domain modulate antigen binding affinity of antibodies?
|
| |
J Clin Invest,
98,
2235-2243.
|
|
|
|
|
|
|
Z.Zhu,
G.Zapata,
R.Shalaby,
B.Snedecor,
H.Chen,
and
P.Carter
(1996).
High level secretion of a humanized bispecific diabody from Escherichia coli.
|
| |
Biotechnology (N Y),
14,
192-196.
|
|
|
|
|
|
|
D.Frishman,
and
P.Argos
(1995).
Knowledge-based protein secondary structure assignment.
|
| |
Proteins,
23,
566-579.
|
|
|
|
|
|
|
A.Zdanov,
Y.Li,
D.R.Bundle,
S.J.Deng,
C.R.MacKenzie,
S.A.Narang,
N.M.Young,
and
M.Cygler
(1994).
Structure of a single-chain antibody variable domain (Fv) fragment complexed with a carbohydrate antigen at 1.7-A resolution.
|
| |
Proc Natl Acad Sci U S A,
91,
6423-6427.
|
|
|
PDB code:
|
|
|
|
|
|
|
|
C.Eigenbrot,
T.Gonzalez,
J.Mayeda,
P.Carter,
W.Werther,
T.Hotaling,
J.Fox,
and
J.Kessler
(1994).
X-ray structures of fragments from binding and nonbinding versions of a humanized anti-CD18 antibody: structural indications of the key role of VH residues 59 to 65.
|
| |
Proteins,
18,
49-62.
|
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PDB codes:
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M.E.Renz,
H.H.Chiu,
S.Jones,
J.Fox,
K.J.Kim,
L.G.Presta,
and
S.Fong
(1994).
Structural requirements for adhesion of soluble recombinant murine vascular cell adhesion molecule-1 to alpha 4 beta 1.
|
| |
J Cell Biol,
125,
1395-1406.
|
|
|
|
|
|
|
M.Malmqvist
(1994).
Kinetic analysis of engineered antibody-antigen interactions.
|
| |
J Mol Recognit,
7,
1-7.
|
|
|
|
|
|
|
M.R.Hurle,
and
M.Gross
(1994).
Protein engineering techniques for antibody humanization.
|
| |
Curr Opin Biotechnol,
5,
428-433.
|
|
|
|
|
|
|
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.
|
| |
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.
|
| |
Trends Biotechnol,
12,
275-279.
|
|
|
|
|
|
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
