1atu
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UNCLEAVED ALPHA-1-ANTITRYPSIN
OverviewOverview
BACKGROUND: 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. RESULTS: 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-antitrypsin is an extended, strand, different from that of the previously determined structure of, another uncleaved alpha1-antitrypsin, and indicates the inherent, flexibility of the loop. CONCLUSIONS: The present structural study, suggests that the uncleaved alpha1-antitrypsin has many folding defects, which can be improved by mutations. These folding defects seem to be, utilized in a coordinated fashion in the regulation of the conformational, switch of alpha1-antitrypsin. Some of the defects, represented by the, Phe51 region and possibly the Met374 and the Thr59 regions, are part of, the sheet-opening mechanism.
DiseaseDisease
Known diseases associated with this structure: Emphysema OMIM:[107400], Emphysema-cirrhosis OMIM:[107400], Hemorrhagic diathesis due to antithrombin Pittsburgh OMIM:[107400], Pulmonary disease, chronic obstructive, susceptibility to OMIM:[107400]
About this StructureAbout this Structure
1ATU is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
ReferenceReference
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., Ryu SE, Choi HJ, Kwon KS, Lee KN, Yu MH, Structure. 1996 Oct 15;4(10):1181-92. PMID:8939743
Page seeded by OCA on Fri Feb 15 15:29:47 2008