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Mechanistic characterization and crystal structure of a small molecule inactivator bound to plasminogen activator inhibitor-1.


ABSTRACT: Plasminogen activator inhibitor type-1 (PAI-1) is a member of the serine protease inhibitor (serpin) family. Excessive PAI-1 activity is associated with human disease, making it an attractive pharmaceutical target. However, like other serpins, PAI-1 has a labile structure, making it a difficult target for the development of small molecule inhibitors, and to date, there are no US Food and Drug Administration-approved small molecule inactivators of any serpins. Here we describe the mechanistic and structural characterization of a high affinity inactivator of PAI-1. This molecule binds to PAI-1 reversibly and acts through an allosteric mechanism that inhibits PAI-1 binding to proteases and to its cofactor vitronectin. The binding site is identified by X-ray crystallography and mutagenesis as a pocket at the interface of ?-sheets B and C and ?-helix H. A similar pocket is present on other serpins, suggesting that this site could be a common target in this structurally conserved protein family.

SUBMITTER: Li SH 

PROVIDER: S-EPMC3870673 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature

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Mechanistic characterization and crystal structure of a small molecule inactivator bound to plasminogen activator inhibitor-1.

Li Shih-Hon SH   Reinke Ashley A AA   Sanders Karen L KL   Emal Cory D CD   Whisstock James C JC   Stuckey Jeanne A JA   Lawrence Daniel A DA  

Proceedings of the National Academy of Sciences of the United States of America 20131202 51


Plasminogen activator inhibitor type-1 (PAI-1) is a member of the serine protease inhibitor (serpin) family. Excessive PAI-1 activity is associated with human disease, making it an attractive pharmaceutical target. However, like other serpins, PAI-1 has a labile structure, making it a difficult target for the development of small molecule inhibitors, and to date, there are no US Food and Drug Administration-approved small molecule inactivators of any serpins. Here we describe the mechanistic and  ...[more]

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