Abstract:
:A heparin-induced conformational change is required to convert antithrombin from a slow to a fast inhibitor of factor Xa. It has been proposed [van Boeckel et al. (1994) Nat. Struct. Biol. 1, 423-425] that the reactive center residue P14 is inserted into beta-sheet A in native antithrombin and is displaced from the beta-sheet by heparin binding, thereby altering the conformation of the reactive center and making it a better target for factor Xa binding. To test this hypothesis, we have characterized a P14 serine --> tryptophan antithrombin variant. From changes in tryptophan fluorescence upon heparin binding, increased affinity for heparin, and partial activation of the variant against factor Xa, we conclude that the proposed mechanism of heparin activation is correct with respect to loop expulsion and that it may consequently be possible to create more highly activated antithrombin variants through suitable hinge region substitutions.
journal_name
Biochemistryjournal_title
Biochemistryauthors
Huntington JA,Olson ST,Fan B,Gettins PGdoi
10.1021/bi9604643subject
Has Abstractpub_date
1996-07-02 00:00:00pages
8495-503issue
26eissn
0006-2960issn
1520-4995pii
bi9604643journal_volume
35pub_type
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