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J. Biol. Chem., Vol. 276, Issue 16, 13077-13086, April 20, 2001

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A Regulatory Hydrophobic Area in the Flexible Joint Region of Plasminogen Activator Inhibitor-1, Defined with Fluorescent Activity-neutralizing Ligands
LIGAND-INDUCED SERPIN POLYMERIZATION^*

Rikke Egelund^§, Anja P. Einholm^§, Katrine E. Pedersen^§, Rasmus W. Nielsen, Anni Christensen, Johanna Deinum^¶, and Peter A. Andreasen

From the  Laboratory of Cellular Protein Science, Department of Molecular and Structural Biology, Aarhus University, 8000 Aarhus C, Denmark, and ^¶ AstraZeneca, R&D Mölndal, 431 83 Mölndal, Sweden

We have characterized the neutralization of the inhibitory activity of the serpin plasminogen activator inhibitor-1 (PAI-1) by a number of structurally distinct organochemicals, including compounds with environment-sensitive spectroscopic properties. In contrast to latent and reactive center-cleaved PAI-1 and PAI-1 in complex with urokinase-type plasminogen activator (uPA), active PAI-1 strongly increased the fluorescence of the PAI-1-neutralizing compounds 1-anilinonaphthalene-8-sulfonic acid and 4,4'-dianilino-1,1'-bisnaphthyl-5,5'-disulfonic acid. The fluorescence increase could be competed by all tested nonfluorescent neutralizers, indicating that all neutralizers bind to a common hydrophobic area preferentially accessible in active PAI-1. Activity neutralization proceeded through two consecutive steps as follows: first step is conversion to forms displaying substrate behavior toward uPA, and second step is to forms inert to uPA. With some neutralizers, the second step was associated with PAI-1 polymerization. Vitronectin reduced the susceptibility to the neutralizers. Changes in sensitivity to activity neutralization by point mutations were compatible with the various neutralizers having overlapping, but not identical, binding sites in the region around -helices D and E and -strand 1A, known to act as a flexible joint when -sheet A opens and the reactive center loop inserts as -strand 4A during reaction with target proteinases. The defined binding area may be a target for development of compounds for neutralizing PAI-1 in cancer and cardiovascular diseases.

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