4G8O: Crystal Structure of a novel small molecule inactivator bound to plasminogen activator inhibitor-1

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.
PDB ID: 4G8ODownload
MMDB ID: 116214
PDB Deposition Date: 2012/7/23
Updated in MMDB: 2013/12
Experimental Method:
x-ray diffraction
Resolution: 2.71  Å
Source Organism:
Similar Structures:
Biological Unit for 4G8O: monomeric; determined by author and by software (PISA)
Molecular Components in 4G8O
Label Count Molecule
Protein (1 molecule)
Plasminogen Activator Inhibitor 1(Gene symbol: SERPINE1)
Molecule annotation
Chemicals (2 molecules)
* Click molecule labels to explore molecular sequence information.

Citing MMDB