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PDBsum entry 2qqo
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Signaling protein
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PDB id
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2qqo
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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 studies of neuropilin/antibody complexes provide insights into semaphorin and vegf binding.
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Authors
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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,
C.Wiesmann.
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Ref.
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EMBO J, 2007,
26,
4902-4912.
[DOI no: ]
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PubMed id
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Abstract
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Neuropilins (Nrps) are co-receptors for class 3 semaphorins and vascular
endothelial growth factors and important for the development of the nervous
system and the vasculature. The extracellular portion of Nrp is composed of two
domains that are essential for semaphorin binding (a1a2), two domains necessary
for VEGF binding (b1b2), and one domain critical for receptor dimerization (c).
We report several crystal structures of Nrp1 and Nrp2 fragments alone and in
complex with antibodies that selectively block either semaphorin or vascular
endothelial growth factor (VEGF) binding. In these structures, Nrps adopt an
unexpected domain arrangement in which the a2, b1, and b2 domains form a tightly
packed core that is only loosely connected to the a1 domain. The locations of
the antibody epitopes together with in vitro experiments indicate that VEGF and
semaphorin do not directly compete for Nrp binding. Based upon our structural
and functional data, we propose possible models for ligand binding to
neuropilins.
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Figure 3.
Figure 3 Overall domain architecture of neuropilins. (A) Domain
organization of Nrp2 (blue, a1; green, a2; yellow, b1; red, b2)
in complex with the Fab fragment of anti-panNrp^A (tan, heavy
chain; gray, light chain). N-glycosylated residues are indicated
in magenta. (B) Ribbon representation of the Nrp a2b1b2
structures; the orange spheres highlight a bound calcium ion.
(C) Superposition of the Nrp2/Fab complex from two different
crystal forms based on the a2b1b2 domains. Note the poor
superposition of the a1 domains (yellow arrows) in comparison to
the a2b1b2 region (black arrows). Structure figures were
produced with PyMol (http://www.pymol.org).
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Figure 5.
Figure 5 Features of the Nrp VEGF- and heparin-binding domains.
(A) The molecular surface of the rat (PDB code 2ORZ) (Vander
Kooi et al, 2007) and human b1b2 crystal structures are colored
as described in Figure 4D. Green arrows indicate an acidic
groove that is formed by the 'spikes' in the b1 domain
(Supplementary Figure S5); this feature forms the
Tuftsin-binding site of rat Nrp1. Yellow arrows indicate the
approximate location of the heparin-binding patch. (B) The
sequence conservation (green, 100%; yellow,  than
or equal to 75%) of the b1b2 domains among 12 Nrps
(Supplementary Figure S3) was mapped onto the surface of the
human Nrp1 b1b2 structure. Two highly conserved patches are
delineated in red. Residues outlined in cyan indicate those
residues that contact the Fab in the anti-Nrp1^B-Fab/b1 complex.
The a2 domain (tan) is shown by using a superposition of the
b1b2 and a2b1b2 structures from Nrp1. (C) Ribbon representation
of the anti-Nrp1^B–Fab/b1 complex (yellow, b1; orange, heavy
chain; gray, light chain). (D) The anti-Nrp1^B/b1 interface. The
b1 domain is depicted as a molecular surface with a green arrow
indicating the Tuftsin/VEGF tail-binding groove. Only CDRs H3
and L1 contact b1.
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The above figures are
reprinted
by permission from Macmillan Publishers Ltd:
EMBO J
(2007,
26,
4902-4912)
copyright 2007.
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