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Contents |
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* Residue conservation analysis
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Enzyme class:
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Chains X, Y:
E.C.2.7.10.1
- receptor protein-tyrosine kinase.
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Reaction:
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L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H+
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L-tyrosyl-[protein]
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+
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ATP
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=
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O-phospho-L-tyrosyl-[protein]
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+
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ADP
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+
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H(+)
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Molecule diagrams generated from .mol files obtained from the
KEGG ftp site
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DOI no:
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Cell
91:695-704
(1997)
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PubMed id:
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Crystal structure at 1.7 A resolution of VEGF in complex with domain 2 of the Flt-1 receptor.
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C.Wiesmann,
G.Fuh,
H.W.Christinger,
C.Eigenbrot,
J.A.Wells,
A.M.de Vos.
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ABSTRACT
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Vascular endothelial growth factor (VEGF) is a homodimeric hormone that induces
proliferation of endothelial cells through binding to the kinase domain receptor
and the Fms-like tyrosine kinase receptor (Flt-1), the extracellular portions of
which consist of seven immunoglobulin domains. We show that the second and third
domains of Flt-1 are necessary and sufficient for binding VEGF with near-native
affinity, and that domain 2 alone binds only 60-fold less tightly than
wild-type. The crystal structure of the complex between VEGF and the second
domain of Flt-1 shows domain 2 in a predominantly hydrophobic interaction with
the "poles" of the VEGF dimer. Based on this structure and on
mutational data, we present a model of VEGF bound to the first four domains of
Flt-1.
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Selected figure(s)
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Figure 2.
Figure 2. Ribbon Rendering of Flt-1[D2], in Two Views
Related by a Rotation of Approximately 90° about the
Vertical AxisThe termini and the secondary structure elements as
defined by the program Procheck ([26]) are labeled; β strands
are rendered as green arrows, the helical turn as a green
ribbon, and the loop regions as gray tubes. The disulfide bond
is shown in ball-and-stick rendering, with sulfur atoms colored
yellow. The two potential N-linked glycosylation sites at
Asn-164 and Asn-196 are colored blue. The VEGF binding site is
located on the “bottom†end of the five-stranded sheet;
residues in contact with VEGF in the complex are colored red. A
segment near the N terminus, which forms strand βa in members
of the I set of the immunoglobulin superfamily, bulges away from
the core of the domain. This figure was created using the
program MOLMOL ( [24]).
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Figure 3.
Figure 3. Stereo Views in Ball-and-Stick Rendering of
Structural DetailsHydrogen bonds are shown as dotted lines;
oxygen atoms are colored red, nitrogens dark blue, and carbons
gray. This figure was generated using the programs MOLSCRIPT
([25]) and RASTER3D ( [29]).(A) The environment of Phe-135 of
Flt-1.(B) The region in Flt-1 corresponding to the “Y
corner†found in most Greek key barrel proteins.(C) A region
of the interface between VEGF (in dark gray) and Flt-1 (in light
gray) around the interaction between Asp-63 and Arg-224, showing
a chain of water molecules in the interface.
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The above figures are
reprinted
by permission from Cell Press:
Cell
(1997,
91,
695-704)
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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L.Yu,
X.H.Liang,
and
N.Ferrara
(2011).
Comparing protein VEGF inhibitors: In vitro biological studies.
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Biochem Biophys Res Commun,
408,
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V.M.Leppänen,
M.Jeltsch,
A.Anisimov,
D.Tvorogov,
K.Aho,
N.Kalkkinen,
P.Toivanen,
S.Ylä-Herttuala,
K.Ballmer-Hofer,
and
K.Alitalo
(2011).
Structural determinants of vascular endothelial growth factor-D receptor binding and specificity.
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Blood,
117,
1507-1515.
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PDB code:
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Z.Ul-Haq,
U.Mahmood,
S.Reza,
R.Uddin,
and
M.Aleem
(2011).
Ligand-Based 3D-QSAR Studies of Diaryl Acyl-sulfonamide Analogues as Human Umbilical Vein Endothelial Cells Inhibitors Stimulated by VEGF.
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Chem Biol Drug Des,
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Anti-SPARC oligopeptide inhibits laser-induced CNV in mice.
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Vision Res,
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L.Claesson-Welsh
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Gremlin: vexing VEGF receptor agonist.
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Blood,
116,
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R.Di Stasi,
D.Diana,
D.Capasso,
R.Palumbo,
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and
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VEGFR1(D2) in drug discovery: Expression and molecular characterization.
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Biopolymers,
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S.Iyer,
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and
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(2010).
Structural insights into the binding of vascular endothelial growth factor-B by VEGFR-1(D2): recognition and specificity.
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J Biol Chem,
285,
23779-23789.
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PDB code:
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V.M.Leppänen,
A.E.Prota,
M.Jeltsch,
A.Anisimov,
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H.Lankinen,
A.Goldman,
K.Ballmer-Hofer,
and
K.Alitalo
(2010).
Structural determinants of growth factor binding and specificity by VEGF receptor 2.
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Proc Natl Acad Sci U S A,
107,
2425-2430.
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PDB codes:
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Y.Yang,
P.Xie,
Y.Opatowsky,
and
J.Schlessinger
(2010).
Direct contacts between extracellular membrane-proximal domains are required for VEGF receptor activation and cell signaling.
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Proc Natl Acad Sci U S A,
107,
1906-1911.
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PDB code:
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A.S.Potty,
K.Kourentzi,
H.Fang,
G.W.Jackson,
X.Zhang,
G.B.Legge,
and
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(2009).
Biophysical characterization of DNA aptamer interactions with vascular endothelial growth factor.
|
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Biopolymers,
91,
145-156.
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E.Stuttfeld,
and
K.Ballmer-Hofer
(2009).
Structure and function of VEGF receptors.
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IUBMB Life,
61,
915-922.
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J.Bostrom,
S.F.Yu,
D.Kan,
B.A.Appleton,
C.V.Lee,
K.Billeci,
W.Man,
F.Peale,
S.Ross,
C.Wiesmann,
and
G.Fuh
(2009).
Variants of the antibody herceptin that interact with HER2 and VEGF at the antigen binding site.
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Science,
323,
1610-1614.
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PDB codes:
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L.K.Ely,
S.Fischer,
and
K.C.Garcia
(2009).
Structural basis of receptor sharing by interleukin 17 cytokines.
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Nat Immunol,
10,
1245-1251.
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PDB code:
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P.I.Toivanen,
T.Nieminen,
L.Viitanen,
A.Alitalo,
M.Roschier,
S.Jauhiainen,
J.E.Markkanen,
O.H.Laitinen,
T.T.Airenne,
T.A.Salminen,
M.S.Johnson,
K.J.Airenne,
and
S.Ylä-Herttuala
(2009).
Novel vascular endothelial growth factor D variants with increased biological activity.
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J Biol Chem,
284,
16037-16048.
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P.Pechan,
H.Rubin,
M.Lukason,
J.Ardinger,
E.DuFresne,
W.W.Hauswirth,
S.C.Wadsworth,
and
A.Scaria
(2009).
Novel anti-VEGF chimeric molecules delivered by AAV vectors for inhibition of retinal neovascularization.
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Gene Ther,
16,
10-16.
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R.J.Albuquerque,
T.Hayashi,
W.G.Cho,
M.E.Kleinman,
S.Dridi,
A.Takeda,
J.Z.Baffi,
K.Yamada,
H.Kaneko,
M.G.Green,
J.Chappell,
J.Wilting,
H.A.Weich,
S.Yamagami,
S.Amano,
N.Mizuki,
J.S.Alexander,
M.L.Peterson,
R.A.Brekken,
M.Hirashima,
S.Capoor,
T.Usui,
B.K.Ambati,
and
J.Ambati
(2009).
Alternatively spliced vascular endothelial growth factor receptor-2 is an essential endogenous inhibitor of lymphatic vessel growth.
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Nat Med,
15,
1023-1030.
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V.Goncalves,
B.Gautier,
F.Huguenot,
P.Leproux,
C.Garbay,
M.Vidal,
and
N.Inguimbert
(2009).
Total chemical synthesis of the D2 domain of human VEGF receptor 1.
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J Pept Sci,
15,
417-422.
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Y.Mirassou,
C.M.Santiveri,
M.J.Pérez de Vega,
R.González-Muñiz,
and
M.A.Jiménez
(2009).
Disulfide bonds versus TrpTrp pairs in irregular beta-hairpins: NMR structure of vammin loop 3-derived peptides as a case study.
|
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Chembiochem,
10,
902-910.
|
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Y.Yamazaki,
Y.Matsunaga,
Y.Tokunaga,
S.Obayashi,
M.Saito,
and
T.Morita
(2009).
Snake venom Vascular Endothelial Growth Factors (VEGF-Fs) exclusively vary their structures and functions among species.
|
| |
J Biol Chem,
284,
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D.G.Udugamasooriya,
C.Ritchie,
R.A.Brekken,
and
T.Kodadek
(2008).
A peptoid antagonist of VEGF receptor 2 recognizes a 'hotspot' in the extracellular domain distinct from the hormone-binding site.
|
| |
Bioorg Med Chem,
16,
6338-6343.
|
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|
|
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|
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F.Mac Gabhann,
and
A.S.Popel
(2008).
Systems biology of vascular endothelial growth factors.
|
| |
Microcirculation,
15,
715-738.
|
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I.G.Muñoz,
F.J.Blanco,
and
G.Montoya
(2008).
On the relevance of defining protein structures in cancer research.
|
| |
Clin Transl Oncol,
10,
204-212.
|
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|
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|
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K.J.Peterson,
J.D.Sadowsky,
E.A.Scheef,
S.Pal,
K.D.Kourentzi,
R.C.Willson,
E.H.Bresnick,
N.Sheibani,
and
S.H.Gellman
(2008).
A fluorescence polarization assay for identifying ligands that bind to vascular endothelial growth factor.
|
| |
Anal Biochem,
378,
8.
|
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|
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|
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S.Ponticelli,
D.Marasco,
V.Tarallo,
R.J.Albuquerque,
S.Mitola,
A.Takeda,
J.M.Stassen,
M.Presta,
J.Ambati,
M.Ruvo,
and
S.De Falco
(2008).
Modulation of angiogenesis by a tetrameric tripeptide that antagonizes vascular endothelial growth factor receptor 1.
|
| |
J Biol Chem,
283,
34250-34259.
|
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|
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|
|
V.Goncalves,
B.Gautier,
C.Garbay,
M.Vidal,
and
N.Inguimbert
(2008).
Structure-based design of a bicyclic peptide antagonist of the vascular endothelial growth factor receptors.
|
| |
J Pept Sci,
14,
767-772.
|
|
|
|
|
|
|
B.A.Appleton,
P.Wu,
J.Maloney,
J.Yin,
W.C.Liang,
S.Stawicki,
K.Mortara,
K.K.Bowman,
J.M.Elliott,
W.Desmarais,
J.F.Bazan,
A.Bagri,
M.Tessier-Lavigne,
A.W.Koch,
Y.Wu,
R.J.Watts,
and
C.Wiesmann
(2007).
Structural studies of neuropilin/antibody complexes provide insights into semaphorin and VEGF binding.
|
| |
EMBO J,
26,
4902-4912.
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PDB codes:
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B.A.Horta,
J.J.Cirino,
and
R.B.de Alencastro
(2007).
Dynamical behavior of the vascular endothelial growth factor: biological implications.
|
| |
Proteins,
67,
517-525.
|
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|
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C.Ruch,
G.Skiniotis,
M.O.Steinmetz,
T.Walz,
and
K.Ballmer-Hofer
(2007).
Structure of a VEGF-VEGF receptor complex determined by electron microscopy.
|
| |
Nat Struct Mol Biol,
14,
249-250.
|
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|
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|
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C.W.Vander Kooi,
M.A.Jusino,
B.Perman,
D.B.Neau,
H.D.Bellamy,
and
D.J.Leahy
(2007).
Structural basis for ligand and heparin binding to neuropilin B domains.
|
| |
Proc Natl Acad Sci U S A,
104,
6152-6157.
|
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PDB codes:
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D.Krilleke,
A.DeErkenez,
W.Schubert,
I.Giri,
G.S.Robinson,
Y.S.Ng,
and
D.T.Shima
(2007).
Molecular mapping and functional characterization of the VEGF164 heparin-binding domain.
|
| |
J Biol Chem,
282,
28045-28056.
|
|
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|
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|
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F.Mac Gabhann,
and
A.S.Popel
(2007).
Dimerization of VEGF receptors and implications for signal transduction: a computational study.
|
| |
Biophys Chem,
128,
125-139.
|
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H.Liu,
X.Chen,
P.J.Focia,
and
X.He
(2007).
Structural basis for stem cell factor-KIT signaling and activation of class III receptor tyrosine kinases.
|
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EMBO J,
26,
891-901.
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PDB codes:
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J.K.Murray,
and
S.H.Gellman
(2007).
Targeting protein-protein interactions: lessons from p53/MDM2.
|
| |
Biopolymers,
88,
657-686.
|
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M.K.Hadden,
and
B.S.Blagg
(2007).
Cytotoxic small molecule dimers and their inhibitory activity against human breast cancer cells.
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| |
Bioorg Med Chem Lett,
17,
5063-5067.
|
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W.D.Tolbert,
J.Daugherty,
C.Gao,
Q.Xie,
C.Miranti,
E.Gherardi,
G.V.Woude,
and
H.E.Xu
(2007).
A mechanistic basis for converting a receptor tyrosine kinase agonist to an antagonist.
|
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Proc Natl Acad Sci U S A,
104,
14592-14597.
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PDB codes:
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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.
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PDB codes:
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L.D.D'Andrea,
A.Del Gatto,
C.Pedone,
and
E.Benedetti
(2006).
Peptide-based molecules in angiogenesis.
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| |
Chem Biol Drug Des,
67,
115-126.
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M.F.Tweedle
(2006).
Adventures in multivalency, the Harry S. Fischer memorial lecture CMR 2005; Evian, France.
|
| |
Contrast Media Mol Imaging,
1,
2-9.
|
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|
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M.Jeltsch,
T.Karpanen,
T.Strandin,
K.Aho,
H.Lankinen,
and
K.Alitalo
(2006).
Vascular endothelial growth factor (VEGF)/VEGF-C mosaic molecules reveal specificity determinants and feature novel receptor binding patterns.
|
| |
J Biol Chem,
281,
12187-12195.
|
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|
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|
|
M.Pieren,
A.E.Prota,
C.Ruch,
D.Kostrewa,
A.Wagner,
K.Biedermann,
F.K.Winkler,
and
K.Ballmer-Hofer
(2006).
Crystal structure of the Orf virus NZ2 variant of vascular endothelial growth factor-E. Implications for receptor specificity.
|
| |
J Biol Chem,
281,
19578-19587.
|
|
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PDB code:
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N.Rahimi
(2006).
Vascular endothelial growth factor receptors: molecular mechanisms of activation and therapeutic potentials.
|
| |
Exp Eye Res,
83,
1005-1016.
|
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S.Cébe-Suarez,
A.Zehnder-Fjällman,
and
K.Ballmer-Hofer
(2006).
The role of VEGF receptors in angiogenesis; complex partnerships.
|
| |
Cell Mol Life Sci,
63,
601-615.
|
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|
S.S.Sidhu,
and
F.A.Fellouse
(2006).
Synthetic therapeutic antibodies.
|
| |
Nat Chem Biol,
2,
682-688.
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W.A.Barton,
D.Tzvetkova-Robev,
E.P.Miranda,
M.V.Kolev,
K.R.Rajashankar,
J.P.Himanen,
and
D.B.Nikolov
(2006).
Crystal structures of the Tie2 receptor ectodomain and the angiopoietin-2-Tie2 complex.
|
| |
Nat Struct Mol Biol,
13,
524-532.
|
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PDB codes:
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W.C.Liang,
X.Wu,
F.V.Peale,
C.V.Lee,
Y.G.Meng,
J.Gutierrez,
L.Fu,
A.K.Malik,
H.P.Gerber,
N.Ferrara,
and
G.Fuh
(2006).
Cross-species vascular endothelial growth factor (VEGF)-blocking antibodies completely inhibit the growth of human tumor xenografts and measure the contribution of stromal VEGF.
|
| |
J Biol Chem,
281,
951-961.
|
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|
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Y.Yamazaki,
and
T.Morita
(2006).
Molecular and functional diversity of vascular endothelial growth factors.
|
| |
Mol Divers,
10,
515-527.
|
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J.H.Lee,
M.D.Canny,
A.De Erkenez,
D.Krilleke,
Y.S.Ng,
D.T.Shima,
A.Pardi,
and
F.Jucker
(2005).
A therapeutic aptamer inhibits angiogenesis by specifically targeting the heparin binding domain of VEGF165.
|
| |
Proc Natl Acad Sci U S A,
102,
18902-18907.
|
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|
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|
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K.Suto,
Y.Yamazaki,
T.Morita,
and
H.Mizuno
(2005).
Crystal structures of novel vascular endothelial growth factors (VEGF) from snake venoms: insight into selective VEGF binding to kinase insert domain-containing receptor but not to fms-like tyrosine kinase-1.
|
| |
J Biol Chem,
280,
2126-2131.
|
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PDB codes:
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L.D.D'Andrea,
G.Iaccarino,
R.Fattorusso,
D.Sorriento,
C.Carannante,
D.Capasso,
B.Trimarco,
and
C.Pedone
(2005).
Targeting angiogenesis: structural characterization and biological properties of a de novo engineered VEGF mimicking peptide.
|
| |
Proc Natl Acad Sci U S A,
102,
14215-14220.
|
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|
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L.J.Reigstad,
J.E.Varhaug,
and
J.R.Lillehaug
(2005).
Structural and functional specificities of PDGF-C and PDGF-D, the novel members of the platelet-derived growth factors family.
|
| |
FEBS J,
272,
5723-5741.
|
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M.Gonçalves,
K.Estieu-Gionnet,
T.Berthelot,
G.Laïn,
M.Bayle,
X.Canron,
N.Betz,
A.Bikfalvi,
and
G.Déléris
(2005).
Design, synthesis, and evaluation of original carriers for targeting vascular endothelial growth factor receptor interactions.
|
| |
Pharm Res,
22,
1411-1421.
|
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S.Nadeau,
J.Baribeau,
A.Janvier,
and
T.Perreault
(2005).
Changes in expression of vascular endothelial growth factor and its receptors in neonatal hypoxia-induced pulmonary hypertension.
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H.W.Christinger,
B.A.Keyt,
and
M.A.Starovasnik
(1998).
Solution structure of the heparin-binding domain of vascular endothelial growth factor.
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Structure,
6,
637-648.
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PDB codes:
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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.
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Structure,
6,
1153-1167.
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PDB code:
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The most recent references are shown first.
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Where a reference describes a PDB structure, the PDB
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shown on the right.
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