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The effect of the Glu342Lys mutation in α1-antitrypsin on its structure, studied by molecular modelling methods.

100%

Jezierski G., Pasenkiewicz-Gierula M.

2001

vol. 48

issue 1

65-75

The structure of native α1-antitrypsin, the most abundant protease inhibitor in human plasma, is characterised primarily by a reactive loop containing the centre of proteinase inhibition, and a β-sheet composed of five strands. Mobility of the reactive loop is confined as a result of electrostatic interactions between side chains of Glu342 and Lys290, both located at the junction of the reactive loop and the β structure. The most common mutation in the protein, resulting in its inactivation, is Glu342→Lys, named the Z mutation. The main goal of this work was to investigate the influence of the Z mutation on the structure of α1-antitrypsin. Commonly used molecular modelling methods have been applied in a comparative study of two protein models: the wild type and the Z mutant. The results indicate that the Z mutation introduces local instabilities in the region of the reactive loop. Moreover, even parts of the protein located far apart from the mutation region are affected. The Z mutation causes a relative change in the total energy of about 3%. Relatively small root mean square differences between the optimised structures of the wild type and the Z mutant, together with detailed analysis of 'conformational searching' process, lead to the hypothesis that the Z mutation principally induces a change in the dynamics of α1-antitrypsin.

Modes of inhibition of cysteine proteases.

75%

Rzychon M., Chmiel D., Stec-Niemczyk J.

vol. 51

issue 4

861-873

Cysteine proteases are involved in many physiological processes and their hyperactivity may lead to severe diseases. Nature has developed various strategies to protect cells and whole organisms against undesired proteolysis. One of them is the control of proteolytic activity by inhibition. This paper presents the mechanisms underlying the action of proteinaceous inhibitors of cysteine proteinases and covers propeptides binding backwards relative to the substrate or distorting the protease catalytic centre similarly to serpins, the p35 protein binding covalently to the enzyme, and cystatins that are exosite binding inhibitors. The paper also discusses tyropins and chagasins that, although unrelated to cystatins, inhibit cysteine proteinases by a similar mechanism, as well as inhibitors of the apoptosis protein family that bind in a direction opposite to that of the substrate, similarly to profragments. Special attention is given to staphostatins, a novel family of inhibitors acting in an unusual manner.

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2 Acta Biochimica Polonica

1 2004

1 2001

1 Chmiel D.

1 Jezierski G.

1 Pasenkiewicz-Gierula M.

1 Rzychon M.

1 Stec-Niemczyk J.

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The effect of the Glu342Lys mutation in α1-antitrypsin on its structure, studied by molecular modelling methods.

Modes of inhibition of cysteine proteases.