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PDBsum entry 1tye
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Cell adhesion
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PDB id
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1tye
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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 basis for allostery in integrins and binding to fibrinogen-Mimetic therapeutics.
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Authors
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T.Xiao,
J.Takagi,
B.S.Coller,
J.H.Wang,
T.A.Springer.
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Ref.
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Nature, 2004,
432,
59-67.
[DOI no: ]
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PubMed id
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Abstract
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Integrins are important adhesion receptors in all Metazoa that transmit
conformational change bidirectionally across the membrane. Integrin alpha and
beta subunits form a head and two long legs in the ectodomain and span the
membrane. Here, we define with crystal structures the atomic basis for
allosteric regulation of the conformation and affinity for ligand of the
integrin ectodomain, and how fibrinogen-mimetic therapeutics bind to platelet
integrin alpha(IIb)beta3. Allostery in the beta3 I domain alters three metal
binding sites, associated loops and alpha1- and alpha7-helices. Piston-like
displacement of the alpha7-helix causes a 62 degrees reorientation between the
beta3 I and hybrid domains. Transmission through the rigidly connected
plexin/semaphorin/integrin (PSI) domain in the upper beta3 leg causes a 70 A
separation between the knees of the alpha and beta legs. Allostery in the head
thus disrupts interaction between the legs in a previously described
low-affinity bent integrin conformation, and leg extension positions the
high-affinity head far above the cell surface.
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Figure 1.
Figure 1: Quaternary rearrangements in the integrin ectodomain.
a -c, Three conformational states visualized in electron
microscopy3,6 and in crystal structures (here and in ref. 7). d
-j, Proposed intermediates in equilibration between known
conformational states. The upper pathways may be stimulated by
ligand binding outside the cell, and the lower pathways by
signals within the cell that separate the  and
 subunit
transmembrane domains. Domains in a -j are shown in solid colour
if known directly from crystal structures, dashed with grey if
placed from crystal structures into electron microscopy image
averages, and in solid grey for EGF-1 and EGF-2, which are
modelled on EGF-3 and EGF-4.
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Figure 3.
Figure 3: The binding sites for ligand-mimetic antagonists and
fibrinogen at the alpha- /
beta- subunit
interface. a, Mapping of fibrinogen binding sensitive
mutations20,49,50 in [IIb]
[3].
C atoms
of fibrinogen-binding sensitive residues are shown as spheres in
the same colour as the domains in which they are present. The
tirofiban-bound structure is shown. b -f, Binding of ligands or
pseudoligands to [IIb]
[3]
(b -e) and binding of (f) cyclo Arg-Gly-Asp-D-Phe-N-methyl-Val
(cyclo RGDfV) to [V]
[3]
(ref. 8). The orientation is identical to that in a. The and
subunits
are shown in magenta and cyan, respectively. Small molecules are
shown as ball-and-stick models with their carbon, nitrogen,
oxygen, sulphur and arsenic atoms coloured yellow, blue, red,
green and grey, respectively. Hydrogen bonds are shown as dotted
lines. Ca^2+ and Mg2+ ions are gold and silver spheres,
respectively. The ligand and S123 coordinations to the MIDAS
metal are shown as thin grey lines.
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The above figures are
reprinted
by permission from Macmillan Publishers Ltd:
Nature
(2004,
432,
59-67)
copyright 2004.
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