Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 110, Issue 51, Pages E4941-E4949Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1216499110
Keywords
fibrinolysis; thrombolysis; fibrosis; cancer
Categories
Funding
- National Institutes of Health [HL55374, NS079639, HL089407]
- US Department of Energy, Office of Science, Office of Basic Energy Sciences [DE-AC02-06CH11357]
- Michigan Technology Tri-Corridor [085P1000817]
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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 beta-sheets B and C and alpha-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.
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