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Canonical Inhibitor-like Interactions Explain Reactivity of α1-Proteinase Inhibitor Pittsburgh and Antithrombin with Proteinases
Ist Teil von
The Journal of biological chemistry, 2003-09, Vol.278 (39), p.37881
Ort / Verlag
American Society for Biochemistry and Molecular Biology
Erscheinungsjahr
2003
Link zum Volltext
Quelle
Electronic Journals Library
Beschreibungen/Notizen
The serpin antithrombin is a slow thrombin inhibitor that requires heparin to enhance its reaction rate. In contrast, α 1 -proteinase inhibitor (α 1 PI) Pittsburgh (P1 Met â Arg natural variant) inhibits thrombin 17 times faster than pentasaccharide heparin-activated antithrombin.
We present here x-ray structures of free and S195A trypsin-bound α 1 PI Pittsburgh, which show that the reactive center loop (RCL) possesses a canonical conformation in the free serpin that does
not change upon binding to S195A trypsin and that contacts the proteinase only between P2 and P2â². By inference from the structure
of heparin cofactor II bound to S195A thrombin, this RCL conformation is also appropriate for binding to thrombin. Reaction
rates of trypsin and thrombin with α 1 PI Pittsburgh and antithrombin and their P2 variants show that the low antithrombin-thrombin reaction rate results from the
antithrombin RCL sequence at P2 and implies that, in solution, the antithrombin RCL must be in a similar canonical conformation
to that found here for α 1 PI Pittsburgh, even in the nonheparin-activated state. This suggests a general, limited, canonical-like interaction between
serpins and proteinases in their Michaelis complexes.
Sprache
Englisch
Identifikatoren
ISSN: 0021-9258
eISSN: 1083-351X
DOI: 10.1074/jbc.M305195200
Titel-ID: cdi_highwire_biochem_278_39_37881
Format
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