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Comment
. 2017 Oct 6;292(40):16521-16522.
doi: 10.1074/jbc.H117.787325.

A novel antithrombin domain dictates the journey's end of a proteinase

Ingrid M Verhamme  1
Affiliations
Comment

A novel antithrombin domain dictates the journey's end of a proteinase

Ingrid M Verhamme. J Biol Chem. .

Abstract

Antithrombin (AT) is an anticoagulant serpin that irreversibly inactivates the clotting proteinases factor Xa and thrombin by forming covalent complexes with them. Mutations in its critical domains, such as those that impair the conformational rearrangement required for proteinase inactivation, increase the risk of venous thrombosis. Águila et al. characterize for the first time the destabilizing effects of mutations in the region of AT that makes contact with the proteinase in the final acyl-enzyme complex. Their work adds new insight into the unique structural intricacies of the inhibitory mechanism.

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Conflict of interest statement

The author declares that she has no conflicts of interest with the contents of this article

Figures

Figure 1.
Figure 1.
Mechanism of proteinase inactivation by serpins. A, Michaelis complex of S195A FXa and AT (Protein Data Bank code 2GD4). B, covalent complex of α1PI with trypsin (Protein Data Bank code 1EZX). Proteinases are shown in purple, serpins are shown in green, RCL are shown in orange. C, mechanism of enzyme (E) and serpin (I) forming a Michaelis complex (EI), acyl-enzyme (EI′), and partitioning between the substrate (k3) and inhibitory pathway (k4). Unstable E-I* complexes dissociate into free E and cleaved I* (k5). D, native AT with positions of Ser365 and Ile207 (orange); L340F, S349P, and H369Y (purple), and three disulfide bridges (blue) (Protein Data Bank code 1E05).
See this image and copyright information in PMC

Comment on

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