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PDBsum entry 1oc0
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Hydrolase/inhibitor
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PDB id
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1oc0
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Contents |
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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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How vitronectin binds pai-1 to modulate fibrinolysis and cell migration.
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Authors
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A.Zhou,
J.A.Huntington,
N.S.Pannu,
R.W.Carrell,
R.J.Read.
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Ref.
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Nat Struct Biol, 2003,
10,
541-544.
[DOI no: ]
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PubMed id
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Abstract
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The interaction of the plasma protein vitronectin with plasminogen activator
inhibitor-1 (PAI-1) is central to human health. Vitronectin binding extends the
lifetime of active PAI-1, which controls hemostasis by inhibiting fibrinolysis
and has also been implicated in angiogenesis. The PAI-1-vitronectin binding
interaction also affects cell adhesion and motility. For these reasons, elevated
PAI-1 activities are associated both with coronary thrombosis and with a poor
prognosis in many cancers. Here we show the crystal structure at a resolution of
2.3 A of the complex of the somatomedin B domain of vitronectin with PAI-1. The
structure of the complex explains how vitronectin binds to and stabilizes the
active conformation of PAI-1. It also explains the tissue effects of PAI-1, as
PAI-1 competes for and sterically blocks the interaction of vitronectin with
cell surface receptors and integrins. Structural understanding of the essential
biological roles of the interaction between PAI-1 and vitronectin opens the
prospect of specifically designed blocking agents for the prevention of
thrombosis and treatment of cancer.
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Figure 1.
Figure 1. Ribbon diagrams of the complex and its components.
(a) Latent PAI-1 (ref. 9). In this structure, the reactive
center loop is inserted as strand 4 (red) of an expanded sheet A
(cyan), changing the shape of the binding site (yellow) for
somatomedin B. (b) The somatomedin B domain (gray with pink
disulfide bridges) binding to the region comprising helix E,
strand 1A and helix F (green) of active PAI-1. Dashed lines
indicate disordered residues in the reactive center loop (RCL)
of PAI-1 and residues leading to the RGD sequence of somatomedin
B. (c) The somatomedin B domain (blue at N terminus to red at C
terminus), showing disulfide bridges (pink) and side chains of
residues that interact with PAI-1. The sequence highlights
disulfide bridges (brackets), residues conserved among mammalian
vitronectin sequences (bold italic), residues with side chains
contacting PAI-1 (red) and the RGD motif (blue). (d) Comparison
of the active (green) and latent (yellow) conformations of PAI-1
showing how the shape of the binding surface changes upon
latency.
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Figure 2.
Figure 2. Stereo view of interacting residues in the PAI-1 -SMB
interface. (a) The region of the somatomedin B domain that
interacts with PAI-1 overlaps extensively with that involved in
the interaction with uPAR, as alanine-scanning mutagenesis has
shown that residues Asp22, Glu23, Leu24, Tyr27 and Tyr28 of
vitronectin (highlighted with magenta bonds) are important for
the interaction with uPAR16. Somatomedin B coloring ranges from
blue at the N terminus to red at the C terminus. (b) Electron
density from the final  [A]-weighted^26
map showing the interaction between helix F (hF) of PAI-1 (gray
bonds) and the loop comprising residues 23 -28 of SMB (pink
bonds). The map is contoured at a level of 1.25  the
r.m.s. electron density. For clarity, contours >2 Å from an atom
in the figure are omitted.
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The above figures are
reprinted
by permission from Macmillan Publishers Ltd:
Nat Struct Biol
(2003,
10,
541-544)
copyright 2003.
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