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* Residue conservation analysis
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References listed in PDB file
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Key reference
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Title
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The crystal structure of placental growth factor in complex with domain 2 of vascular endothelial growth factor receptor-1.
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Authors
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H.W.Christinger,
G.Fuh,
A.M.De vos,
C.Wiesmann.
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Ref.
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J Biol Chem, 2004,
279,
10382-10388.
[DOI no: ]
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PubMed id
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Abstract
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Placental growth factor (PlGF) is a member of the vascular endothelial growth
factor (VEGF) family and plays an important role in pathological angiogenic
events. PlGF exerts its biological activities through binding to VEGFR1, a
receptor tyrosine kinase that consists of seven immunoglobulin-like domains in
its extracellular portion. Here we report the crystal structure of PlGF bound to
the second immunoglobulin-like domain of VEGFR1 at 2.5 A resolution and compare
the complex to the closely related structure of VEGF bound to the same receptor
domain. The two growth factors, PlGF and VEGF, share a sequence identity of
approximately 50%. Despite this moderate sequence conservation, they bind to the
same binding interface of VEGFR1 in a very similar fashion, suggesting that both
growth factors could induce very similar if not identical signaling events.
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Figure 5.
FIG. 5. Sequence alignment of the PlGF and VEGF
receptor-binding domain. Secondary structure elements are
depicted at the top with dark gray arrows referring to  -strands
and light gray boxes to  -helices. Numbers at
top refer to human PlGF and numbers at bottom to human VEGF
sequence. green, strictly conserved in all shown sequences;
yellow, conserved in VEGF or PlGF only; orange, conserved among
PlGF and among VEGF as different residues; bold font, monomer 1
receptor binding interface; bold font and underlined, monomer 2
receptor binding interface; boxed residues, core of receptor
interface; italics, residues involved in dimer interface.
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Figure 6.
FIG. 6. Schematic representation of VEGF and PlGF homo- and
heterodimers. A, PlGF homodimer; B, VEGF homodimer; C, PlGF/VEGF
heterodimer. Note the asymmetric nature of the PlGF/VEGF
heterodimer.
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The above figures are
reprinted
by permission from the ASBMB:
J Biol Chem
(2004,
279,
10382-10388)
copyright 2004.
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Secondary reference #1
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Title
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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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Authors
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C.Wiesmann,
G.Fuh,
H.W.Christinger,
C.Eigenbrot,
J.A.Wells,
A.M.De vos.
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Ref.
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Cell, 1997,
91,
695-704.
[DOI no: ]
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PubMed id
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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
reproduced from the cited reference
with permission from Cell Press
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Secondary reference #2
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Title
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The crystal structure of human placenta growth factor-1 (plgf-1), An angiogenic protein, At 2.0 a resolution.
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Authors
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S.Iyer,
D.D.Leonidas,
G.J.Swaminathan,
D.Maglione,
M.Battisti,
M.Tucci,
M.G.Persico,
K.R.Acharya.
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Ref.
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J Biol Chem, 2001,
276,
12153-12161.
[DOI no: ]
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PubMed id
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Figure 1.
Fig. 1. Structural comparison of PlGF-1 and other members
of the cysteine-knot super family. A, representation of the
PlGF-1 homodimer structure. Disulfide bonds are shown in a
ball-and-stick representation. The inset presents the
organization of three intra- (in yellow) and one interdisulfide
bridge (in green) in the cysteine-knot motif. Each monomer in
the homodimer is colored differently to enhance clarity. Orange,
monomer A; cyan, monomer B. B, representatives of known
structures from the cysteine-knot protein family of dimeric
molecules. a, VEGF (PDB code 2VPF, Ref. 39); b, PDGF-BB (PDB
code 1PDG, Ref. 51); c, TGF-  2 (PDB code
1TFG, Ref. 52); and d, NGF (PDB code 1BTG, Ref. 53). With the
exception of NGF, the homodimer 2-fold axis is perpendicular to
the plane of the -sheet. The
cysteine knots are highlighted. C, structure-based sequence
alignment of PlGF-1 with VEGF (38, 39). Amino acid residues that
form part of the secondary structural elements ( -strands and
helices) as determined by DSSP (60) are shown in blue and red,
respectively. The cysteine residues are shaded pink. VEGF
residues involved in Flt-1 (VEGFR-1) binding (40), and the
equivalent residues in PlGF-1 (based on a modeling study) are
boxed and shaded in yellow. The conserved glycine residue in
both structures is underlined. This figure was created with the
program ALSCRIPT (61). D, stereo view displaying the C  traces of
PlGF-1 (orange) and VEGF (cyan) (39) homodimers after alignment
of the two structures with the program "O" (49). A, B, and D
were created with the program MOLSCRIPT (59).
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Figure 2.
Fig. 2. Proposed model for the PlGF-1·Flt-1[D2]
complex based on the crystal structures of PlGF-1 (present
study) and the VEGF·Flt-1[D2] complex (40), PDB accession
code 1FLT. A, PlGF-1 homodimer is shown in orange (molecule A)
and cyan (molecule B), whereas the Flt-1[D2] molecules are shown
in purple and green. B, stereo views of contact residues (C atoms plus
sidechain atoms) at the putative PlGF-1·Flt-1[D2]
interface. Residues from PlGF-1 monomers A and B are marked in
orange and cyan, respectively. Residues from Flt-1 (figure based
on model shown in A) are colored in green. The sidechains for
Glu73 and Asn74 in free PlGF-1 are disordered and hence are
treated as alanines. C, stereo views of contact residues (C atoms plus
sidechain atoms) for PlGF-1. Residues from monomer A and B are
marked in orange and cyan, respectively (figure based on model
shown in A). The sidechains for Glu73 and Asn74 in free PlGF-1
are disordered and hence are treated as alanines. D, stereo
views of contact residues (C atoms plus
sidechain atoms) for Flt-1[D2] (figure based on model shown in
A). E, stereo views showing the location of the groove in PlGF-1
(residues Asp72, Glu73, Val52, Met55, Val45, Asp43, and Ser59)
and VEGF (Asp63, Glu64, Ile^43, Ile^46, Phe^36, Asp34, and
Ser50), implicated for recognition of domain 3 of Flt-1 (40).
The figure also shows the difference in conformation for segment
90-95 in PlGF-1 and 81-86 in VEGF. Residues Ile^83, Lys84, and
Pro85 are implicated in KDR recognition in VEGF (38), and the
corresponding residues in PlGF-1 are Ile^92, Ser94, and Arg93.
The sidechains for PIGF-1 and VEGF are shown in orange and cyan,
respectively. Ser94 and Glu73 in the PlGF-1 structure are
represented as alanines because of insufficient electron density
beyond the C atom. A-E
was generated using MOLSCRIPT (59).
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The above figures are
reproduced from the cited reference
with permission from the ASBMB
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