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PDBsum entry 2vdo
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Cell adhesion/immune system
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PDB id
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2vdo
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Contents |
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452 a.a.
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455 a.a.
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12 a.a.
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219 a.a.
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214 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 basis for distinctive recognition of fibrinogen gammac peptide by the platelet integrin alphaiibbeta3.
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Authors
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T.A.Springer,
J.Zhu,
T.Xiao.
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Ref.
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J Cell Biol, 2008,
182,
791-800.
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PubMed id
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Abstract
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Hemostasis and thrombosis (blood clotting) involve fibrinogen binding to
integrin alpha(IIb)beta(3) on platelets, resulting in platelet aggregation.
alpha(v)beta(3) binds fibrinogen via an Arg-Asp-Gly (RGD) motif in fibrinogen's
alpha subunit. alpha(IIb)beta(3) also binds to fibrinogen; however, it does so
via an unstructured RGD-lacking C-terminal region of the gamma subunit (gammaC
peptide). These distinct modes of fibrinogen binding enable alpha(IIb)beta(3)
and alpha(v)beta(3) to function cooperatively in hemostasis. In this study,
crystal structures reveal the integrin alpha(IIb)beta(3)-gammaC peptide
interface, and, for comparison, integrin alpha(IIb)beta(3) bound to a lamprey
gammaC primordial RGD motif. Compared with RGD, the GAKQAGDV motif in gammaC
adopts a different backbone configuration and binds over a more extended region.
The integrin metal ion-dependent adhesion site (MIDAS) Mg(2+) ion binds the
gammaC Asp side chain. The adjacent to MIDAS (ADMIDAS) Ca(2+) ion binds the
gammaC C terminus, revealing a contribution for ADMIDAS in ligand binding.
Structural data from this natively disordered gammaC peptide enhances our
understanding of the involvement of gammaC peptide and integrin
alpha(IIb)beta(3) in hemostasis and thrombosis.
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Secondary reference #1
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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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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
reproduced from the cited reference
with permission from Macmillan Publishers Ltd
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