 |
PDBsum entry 1ijb
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Blood clotting
|
PDB id
|
|
|
|
1ijb
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
Contents |
 |
|
|
|
|
|
|
|
|
|
|
* Residue conservation analysis
|
|
|
|
|
References listed in PDB file
|
|
|
Key reference
|
|
|
Title
|
|
Structural basis of von willebrand factor activation by the snake toxin botrocetin.
|
|
|
Authors
|
|
K.Fukuda,
T.A.Doggett,
L.A.Bankston,
M.A.Cruz,
T.G.Diacovo,
R.C.Liddington.
|
|
|
Ref.
|
|
Structure, 2002,
10,
943-950.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
Abstract
|
|
|
The A1 domain of von Willebrand factor (vWF) mediates platelet adhesion to sites
of vascular injury by binding to the platelet receptor glycoprotein Ib (GpIb),
an interaction that is regulated by hydrodynamic shear forces. The GpIb binding
surface of A1 is distinct from a regulatory region, suggesting that ligand
binding is controlled allosterically. Here we report the crystal structures of
the "gain-of-function" mutant A1 domain (I546V) and its complex with
the exogenous activator botrocetin. We show that botrocetin switches the mutant
A1 back toward the wild-type conformation, suggesting that affinity is enhanced
by augmenting the GpIb binding surface rather than through allosteric control.
Functional studies of platelet adhesion under flow further suggest that the
activation mechanism is distinct from that of the gain-of-function mutation.
|
|
|
|
|
|
Figure 3.
Figure 3. Structure of the A1-Botrocetin Complex(A) Stereo
view (Ca tracing) of the complex. The current model includes 199
residues from 502 to 700 of the mutant A1 domain, 133 (119)
residues of the a (b) subunits of botrocetin, and 94 water
molecules. There is no electron density for the loop (residues
55-60 in the b subunit). The A1 domain is in blue; the a and b
subunits of botrocetin are in pink and green, respectively.
Gain-of-function mutations are shown as blue balls;
loss-of-function mutations are shown in red; loss of botrocetin
binding mutations are shown in yellow. The I546V mutation site
is shown as a green ball.(B) Space-filling model of the complex
with mutation sites indicated; same view as in (A). The NMC-4
antibody (V[H]-V[L] dimer) is shown as a semitransparent
molecular surface.(C) Electrostatic surface potential contoured
from -15 (red) to +15 (blue) kT e^ -1. The figure was made using
RASTER3D [30] and GRASP [32].
|
|
|
|
|
|
The above figure is
reprinted
by permission from Cell Press:
Structure
(2002,
10,
943-950)
copyright 2002.
|
|
|
|
|
|
|
