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The anticoagulant activation of antithrombin by heparin

Jin, Lei and Abrahams, Jan Pieter and Skinner, Richard and Petitou, Maurice and Pike, Robert N. and Carrell, Robin W.. (1997) The anticoagulant activation of antithrombin by heparin. Proceedings of the National Academy of Sciences of the United States of America, 94 (26). pp. 14683-14688.

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Official URL: https://edoc.unibas.ch/76006/

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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-Angstrom 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-ll 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.
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Structural Biology & Biophysics > Nano-diffraction of Biological Specimen (Abrahams)
UniBasel Contributors:Abrahams, Jan Pieter
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:National Academy of Sciences
ISSN:0027-8424
e-ISSN:1091-6490
Note:Publication type according to Uni Basel Research Database: Journal article
Identification Number:
Last Modified:05 Nov 2020 15:07
Deposited On:05 Nov 2020 15:07

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