1e03

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spinqualitylabelsall models 1e03, resolution 2.9Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

PLASMA ALPHA ANTITHROMBIN-III AND PENTASACCHARIDE

Overview

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.

About this Structure

1E03 is a Single protein structure of sequence from Homo sapiens with NAG and NTP as ligands. Full crystallographic information is available from OCA.

Reference

The anticoagulant activation of antithrombin by heparin., Jin L, Abrahams JP, Skinner R, Petitou M, Pike RN, Carrell RW, Proc Natl Acad Sci U S A. 1997 Dec 23;94(26):14683-8. PMID:9405673

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