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Introduction

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This update summarizes recent advances in the structure, mechanism, and physiology of antithrombin (gene symbol SERPINC1) and heparin cofactor II (gene symbol SERPIND1, alias HCF2). Current recommendations for treatment of inherited and acquired antithrombin deficiency are reviewed elsewhere.1 A database of antithrombin mutations is available online (http://www1.imperial.ac.uk/departmentofmedicine/divisions/experimentalmedicine/haematology/coag/antithrombin/).

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Antithrombin

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Mechanism of Action of Antithrombin
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General Serpin Mechanism
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Recent studies have clarified the mechanism by which serpins inhibit their target proteases.2 In the first step of this mechanism, the reactive site of the serpin docks with the catalytic site of the protease to form an encounter (Michaelis) complex. Once the encounter complex has formed, the P1-P1′ peptide bond in the reactive site of the serpin undergoes nucleophilic attack by the serine hydroxyl group in the catalytic triad of the protease, resulting in cleavage of the peptide bond and formation of a covalent acyl bond between the hydroxyl group and the carbonyl group of the P1 residue.

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What happens next was demonstrated by crystallization of the covalent complex of α 1-antitrypsin with trypsin.3 In this complex, the entire reactive-site loop, with trypsin still covalently attached to the P1 methionine, is incorporated into β-sheet A to form a structure that closely resembles the cleaved form of α 1-antitrypsin shown in Fig. 176-2. Translocation of the P1 residue to the opposite pole of the serpin disrupts the catalytic triad, preventing deacylation and release of trypsin from the complex. Other regions of the protease also become disordered as they are crushed against the body of the serpin, and these regions appear to be susceptible to proteolytic degradation (Fig. 176S-6). Thus proteolytic cleavage of the serpin by its target protease results in a striking rearrangement of the serpin’s reactive site, producing inhibition by deformation of the protease.

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Fig. 176S-6

Serpin mechanism. The structures of native trypsin (Protein Data Bank ID No. 1TPP) and native α 1-antitrypsin (Protein Data Bank ID No. 1PSI) are shown on the left. The covalent complex (Protein Data Bank ID No. 1EZX) is shown on the right. In the first step of the reaction, trypsin cleaves the P1-P1' peptide bond in the reactive-site loop of α 1-antitrypsin (the P1 through P17 residues are colored yellow). The cleaved loop then rapidly inserts itself into β-sheet A to assume a more stable conformation. Trypsin remains covalently linked to the P1 residue by an acyl bond and becomes translocated to the opposite pole of the serpin. This results in disruption of the catalytic triad, which prevents deacylation and release of trypsin from the complex. Secondary-structure elements are colored as follows: α-helix, green; β-strand, brown; others, blue. Regions of disordered structure in complexed trypsin are indicated by the dashed red lines. All structures were rendered with Cn3D version 4.1 (www.ncbi.nlm.nih.gov).

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