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PDBsum entry 2x1w
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Hormone/signaling protein
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PDB id
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2x1w
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Contents |
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98 a.a.
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196 a.a.
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179 a.a.
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193 a.a.
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References listed in PDB file
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Key reference
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Title
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Structural determinants of growth factor binding and specificity by vegf receptor 2.
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Authors
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V.M.Leppänen,
A.E.Prota,
M.Jeltsch,
A.Anisimov,
N.Kalkkinen,
T.Strandin,
H.Lankinen,
A.Goldman,
K.Ballmer-Hofer,
K.Alitalo.
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Ref.
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Proc Natl Acad Sci U S A, 2010,
107,
2425-2430.
[DOI no: ]
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PubMed id
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Abstract
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Vascular endothelial growth factors (VEGFs) regulate blood and lymph vessel
formation through activation of three receptor tyrosine kinases, VEGFR-1, -2,
and -3. The extracellular domain of VEGF receptors consists of seven
immunoglobulin homology domains, which, upon ligand binding, promote receptor
dimerization. Dimerization initiates transmembrane signaling, which activates
the intracellular tyrosine kinase domain of the receptor. VEGF-C stimulates
lymphangiogenesis and contributes to pathological angiogenesis via VEGFR-3.
However, proteolytically processed VEGF-C also stimulates VEGFR-2, the
predominant transducer of signals required for physiological and pathological
angiogenesis. Here we present the crystal structure of VEGF-C bound to the
VEGFR-2 high-affinity-binding site, which consists of immunoglobulin homology
domains D2 and D3. This structure reveals a symmetrical 22 complex, in which
left-handed twisted receptor domains wrap around the 2-fold axis of VEGF-C. In
the VEGFs, receptor specificity is determined by an N-terminal alpha helix and
three peptide loops. Our structure shows that two of these loops in VEGF-C bind
to VEGFR-2 subdomains D2 and D3, while one interacts primarily with D3.
Additionally, the N-terminal helix of VEGF-C interacts with D2, and the groove
separating the two VEGF-C monomers binds to the D2/D3 linker. VEGF-C, unlike
VEGF-A, does not bind VEGFR-1. We therefore created VEGFR-1/VEGFR-2 chimeric
proteins to further study receptor specificity. This biochemical analysis,
together with our structural data, defined VEGFR-2 residues critical for the
binding of VEGF-A and VEGF-C. Our results provide significant insights into the
structural features that determine the high affinity and specificity of
VEGF/VEGFR interactions.
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Figure 1.
Structure of the VEGF-C/VEGFR-2D23 complex in a cartoon
representation. The VEGF-C homodimer is shown in orange and
green, and the two VEGFR-2 receptor chains are colored in light
blue. The sugar moieties and the disulfide bonds are shown in
purple and yellow sticks, respectively. VEGF-C binds to the
VEGFR-2 interface between domains 2 and 3.
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Figure 2.
Interface between VEGF-C and VEGFR-2. (A) VEGF-C binding
interface on VEGFR-2. VEGFR-2 is shown as a cartoon
representation with the VEGF-C binding key residues highlighted
in sticks and labeled. (B) An overview of the VEGF-C/VEGFR-2D23
site 1 interface, with VEGF-C monomer A colored in green and
VEGF-C residues at the interface labeled. VEGFR-2 charge
distribution shown as a surface potential model. (C) The same as
in (B) for the site 2 interface with VEGF-C monomer B in orange
and the monomer 2 key residues labeled. (D) VEGF-C Asp123
interactions with VEGFR-2. Hydrogen bonds and salt bridges are
shown in gray dashed lines. (E) VEGF-C Glu169 interactions with
VEGFR-2 as in (D). (F) VEGF-C Thr148 and Asn149 interactions
with VEGFR-2 as in (D).
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