 |
PDBsum entry 1azx
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Serine protease inhibitor
|
PDB id
|
|
|
|
1azx
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
Contents |
 |
|
|
|
|
|
|
|
|
|
|
* Residue conservation analysis
|
|
|
|
|
References listed in PDB file
|
|
|
Key reference
|
|
|
Title
|
|
The anticoagulant activation of antithrombin by heparin.
|
|
|
Authors
|
|
L.Jin,
J.P.Abrahams,
R.Skinner,
M.Petitou,
R.N.Pike,
R.W.Carrell.
|
|
|
Ref.
|
|
Proc Natl Acad Sci U S A, 1997,
94,
14683-14688.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
Abstract
|
|
|
Antithrombin, a plasma serpin, is relatively inactive as an inhibitor of the
coagulation proteases until it binds to the heparan side chains that line the
microvasculature. The binding specifically occurs to a core pentasaccharide
present both in the heparans and in their therapeutic derivative heparin. The
accompanying conformational change of antithrombin is revealed in a 2.9-A
structure of a dimer of latent and active antithrombins, each in complex with
the high-affinity pentasaccharide. Inhibitory activation results from a shift in
the main sheet of the molecule from a partially six-stranded to a five-stranded
form, with extrusion of the reactive center loop to give a more exposed
orientation. There is a tilting and elongation of helix D with the formation of
a 2-turn helix P between the C and D helices. Concomitant conformational changes
at the heparin binding site explain both the initial tight binding of
antithrombin to the heparans and the subsequent release of the
antithrombin-protease complex into the circulation. The pentasaccharide binds by
hydrogen bonding of its sulfates and carboxylates to Arg-129 and Lys-125 in the
D-helix, to Arg-46 and Arg-47 in the A-helix, to Lys-114 and Glu-113 in the
P-helix, and to Lys-11 and Arg-13 in a cleft formed by the amino terminus. This
clear definition of the binding site will provide a structural basis for
developing heparin analogues that are more specific toward their intended target
antithrombin and therefore less likely to exhibit side effects.
|
|
|
|
|
|
|
|
Figure 1.
Fig. 1. Schematic: i, circulating antithrombin; ii, contacts
endothelial heparans with induction of high-affinity binding and
reactive^ site loop exposure; iii-iv, complexes with factor Xa
followed^ by loop cleavage and insertion with diminished heparin
affinity; and v, the complex is released into the circulation
for catabolism by the liver.
|
|
Figure 3.
Fig. 3. Ribbon diagrams of (from left) I-antithrombin (15),
pentasaccharide-complexed I-antithrombin, and  [1]-antitrypsin
(32). The pentasaccharide activation of I-antithrombin is seen
to involve^ a closing of the A-sheet (magenta), an extension
(blue) of helix D (yellow), and an expulsion of residues P[14]
(green sphere) and^ P[15] (black sphere) of the reactive site
loop (red). The reactive^ loop of both antithrombin molecules is
constrained by the dimer contact (see Fig. 2a) of the  -pleated
P[3]-P[8] (ribboned arrow). An indication of the likely free
conformation, with exposure of^ the P[1] reactive center (shown
as a ball-stick model), is provided^ by the optimal inhibitory
conformation of the reactive loop present in [1]-antitrypsin
(32).
|
|
|
|
|
|
|
|
|
|
