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PDBsum entry 1gwb
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Blood clotting
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PDB id
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1gwb
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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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Crystal structure of the platelet glycoprotein ib(alpha) n-Terminal domain reveals an unmasking mechanism for receptor activation.
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Authors
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S.Uff,
J.M.Clemetson,
T.Harrison,
K.J.Clemetson,
J.Emsley.
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Ref.
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J Biol Chem, 2002,
277,
35657-35663.
[DOI no: ]
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PubMed id
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Abstract
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Glycoprotein Ib (GPIb) is a platelet receptor with a critical role in mediating
the arrest of platelets at sites of vascular damage. GPIb binds to the A1 domain
of von Willebrand factor (vWF-A1) at high blood shear, initiating platelet
adhesion and contributing to the formation of a thrombus. To investigate the
molecular basis of GPIb regulation and ligand binding, we have determined the
structure of the N-terminal domain of the GPIb(alpha) chain (residues 1-279).
This structure is the first determined from the cell adhesion/signaling class of
leucine-rich repeat (LRR) proteins and reveals the topology of the
characteristic disulfide-bonded flanking regions. The fold consists of an
N-terminal beta-hairpin, eight leucine-rich repeats, a disulfide-bonded loop,
and a C-terminal anionic region. The structure also demonstrates a novel LRR
motif in the form of an M-shaped arrangement of three tandem beta-turns.
Negatively charged binding surfaces on the LRR concave face and anionic region
indicate two-step binding kinetics to vWF-A1, which can be regulated by an
unmasking mechanism involving conformational change of a key loop. Using
molecular docking of the GPIb and vWF-A1 crystal structures, we were also able
to model the GPIb.vWF-A1 complex.
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Figure 1.
Fig. 1. Overall topology of the GPIb  N-terminal
domain. Ribbon diagram of the topology viewed from the side and
a 90° rotated view facing the concave surface of the
leucine-rich repeats are shown. The three short 3[10] helices
are colored light blue, and the helix in
the C-terminal flank is colored dark blue. Convex face  -strands are
colored green, and concave face -strands are
colored gray. Five expressed BSS mutations, which cause loss of
vWF binding, are shown as black balls. L57F and C65R localize to
LRR2 with L129P, A156V, and L179del localized to the LRR5, LRR6,
and LRR7 -strands
respectively. The regulatory (R)-loop is colored orange with
activating platelet-type von Willebrand disease mutations G233V
and M239V indicated as orange balls. The anionic region is
colored red with the molecular structure of the sulfated
tyrosine residues 276, 278, and 279 shown in full.
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Figure 3.
Fig. 3. Fine structure of the GPIb R-loop and
anionic region. a and b, the R-loop and -strands
from the concave face viewed from two orientations related by
90° rotation are shown. Key residues are labeled including
platelet-type von Willebrand disease mutations G233V and M239V
and the Bernard-Soulier syndrome mutation A156V. c, fine
structure of the GPIb anionic
region. Key residues in the anionic region (residues 269-279)
are indicated showing the interactions with the disulfide loop
and -turn repeat
motif from LRR8. The backbone of the anionic region is colored
red, the disulfide loop is colored dark green, and the LRR8 is
colored blue. Key hydrogen bonding/electrostatic interactions
are indicated as dotted blue lines.
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The above figures are
reprinted
by permission from the ASBMB:
J Biol Chem
(2002,
277,
35657-35663)
copyright 2002.
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