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

• Authors: Grzegorz Jezierski , Marta Pasenkiewicz-Gierula
• Languages of publication: EN

Abstracts

EN

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.

Keywords

EN

serpins   protein structure   energy minimisation   molecular dynamics simulation  

• Publisher: Polish Biochemical Society
• Journal: Acta Biochimica Polonica
• Year: 2001
• Volume: 48
• Issue: 1
• Pages: 65-75

Dates

published

2001

revised

2001-01-26

received

2001-01-8

accepted

2001-02-6

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