ABSTRACT
Alpha-1-antitrypsin is the archetypal member of the serine proteinase inhibitor or serpin superfamily. The structure of the serpins is based on three beta-sheets and nine beta-helices. This structure supports an exposed mobile reactive loop that presents a peptide sequence as a pseudosubstrate for the target proteinase. After docking the proteinase is inactivated by a mousetrap action that swings it from the top to the bottom of the protein in association with the insertion of an extra strand in beta-sheet A. The structure of the serpins is very much a dual edged sword in that it is central to their role as effective antiproteinases but also renders them liable to undergo conformational change in association with disease. The process of disease related polymerisation is most strikingly displayed by the inclusion body dementia, familial encephalopathy with neuroserpin inclusion bodies. The serpinopathies underlie a range of diseases as diverse as cirrhosis, thrombosis, angio-oedema and dementia.
