The native strains in the hydrophobic core and flexible reactive loop of a serine protease inhibitor: crystal structure of an uncleaved alpha1-antitrypsin at 2.7 A

Structure
S E RyuM H Yu

Abstract

The protein alpha1-antitrypsin is a prototype member of the serpin (serine protease inhibitor) family and is known to inhibit the activity of neutrophil elastase in the lower respiratory tract. Members of this family undergo a large structural rearrangement upon binding to a target protease, involving cleavage of the reactive-site loop. This loop is then inserted into the main body of the enzyme following the opening of a central beta sheet, leading to stabilization of the structure. Random mutageneses of alpha1-antitrypsin identified various mutations that stabilize the native structure and retard the insertion of the reactive-site loop. Structural studies of these mutations may reveal the mechanism of the conformational change. We have determined the three-dimensional structure of an uncleaved alpha1-antitrypsin with seven such stabilizing mutations (hepta alpha1-antitrypsin) at 2.7 A resolution. From the comparison of the structure with other serpin structures, we found that hepta alpha1-antitrypsin is stabilized due to the release of various strains that exist in native wild type alpha1-antitrypsin, including unfavorable hydrophobic interactions in the central hydrophobic core. The reactive-site loop of hepta alpha1-antitry...Continue Reading

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