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

Proc Natl Acad Sci U S A. 2013 Dec 17;110(51):E4941-9. doi: 10.1073/pnas.1216499110. Epub 2013 Dec 2.

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 β-sheets B and C and α-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.

Keywords: cancer; fibrinolysis; fibrosis; thrombolysis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Allosteric Regulation
  • Crystallography, X-Ray
  • Humans
  • Plasminogen Activator Inhibitor 1 / chemistry*
  • Plasminogen Activator Inhibitor 1 / genetics
  • Plasminogen Activator Inhibitor 1 / metabolism
  • Protein Binding
  • Protein Structure, Secondary
  • Protein Structure, Tertiary
  • Structure-Activity Relationship
  • Vitronectin / chemistry
  • Vitronectin / genetics
  • Vitronectin / metabolism

Substances

  • Plasminogen Activator Inhibitor 1
  • SERPINE1 protein, human
  • Vitronectin

Associated data

  • PDB/4G8O
  • PDB/4G8R