 |
PDBsum entry 1sr5
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Hydrolase/hydrolase inhibitor
|
PDB id
|
|
|
|
1sr5
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
Contents |
 |
|
|
|
|
|
|
|
|
|
|
|
409 a.a.
|
|
|
|
|
|
|
|
|
|
|
32 a.a.
|
|
|
|
|
|
|
|
|
|
|
248 a.a.
|
|
|
|
|
|
|
|
|
|
|
* Residue conservation analysis
|
|
|
|
|
References listed in PDB file
|
|
|
Key reference
|
|
|
Title
|
|
The ternary complex of antithrombin-Anhydrothrombin-Heparin reveals the basis of inhibitor specificity.
|
|
|
Authors
|
|
A.Dementiev,
M.Petitou,
J.M.Herbert,
P.G.Gettins.
|
|
|
Ref.
|
|
Nat Struct Mol Biol, 2004,
11,
863-867.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
Abstract
|
|
|
Antithrombin, the principal physiological inhibitor of the blood coagulation
proteinase thrombin, requires heparin as a cofactor. We report the crystal
structure of the rate-determining encounter complex formed between antithrombin,
anhydrothrombin and an optimal synthetic 16-mer oligosaccharide. The
antithrombin reactive center loop projects from the serpin body and adopts a
canonical conformation that makes extensive backbone and side chain contacts
from P5 to P6' with thrombin's restrictive specificity pockets, including
residues in the 60-loop. These contacts rationalize many earlier mutagenesis
studies on thrombin specificity. The 16-mer oligosaccharide is just long enough
to form the predicted bridge between the high-affinity pentasaccharide-binding
site on antithrombin and the highly basic exosite 2 on thrombin, validating the
design strategy for this synthetic heparin. The protein-protein and
protein-oligosaccharide interactions together explain the basis for heparin
activation of antithrombin as a thrombin inhibitor.
|
|
|
|
|
|
|
|
Figure 2.
Figure 2. Stereo ribbon representation of the ternary complex.
Antithrombin is gold, with the exception of the reactive center
loop (cyan). Thrombin is red and the 16-mer heparin is in stick
form, with those residues that are visible in the electron
density in black and those that are modeled in green.
|
|
Figure 3.
Figure 3. The antithrombin reactive center loop conformation and
contacts with thrombin. (a) Stereo view of the antithrombin
RCL from P7 to P6' (ball and stick) interacting with the surface
of thrombin portrayed using GRASP. The residues P7 to P6' are
Ala-Val-Val-Ile-Ala-Gly-Arg-Ser-Leu-Asn-Pro-Asn (the scissile
P1-P1' residues are underlined). (b) Stereo view of contacts
between the antithrombin RCL from P7 to P6' (cyan) and residues
in and around the thrombin active site (green), using a
transparent view of the thrombin surface (gray). The orientation
is the same in both views.
|
|
|
|
|
|
The above figures are
reprinted
by permission from Macmillan Publishers Ltd:
Nat Struct Mol Biol
(2004,
11,
863-867)
copyright 2004.
|
|
|
|
|
|
|
