4G8O

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

Summary for 4G8O

• Entry DOI: 10.2210/pdb4g8o/pdb
• Related: 1B3K 4G8R
• Descriptor: Plasminogen activator inhibitor 1, SULFATE ION, 1,2-ETHANEDIOL, ... (5 entities in total)
• Functional Keywords: serpin, pai-1, inhibitor, blood clotting, blood clotting-inhibitor complex, blood clotting/inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Secreted: P05121
• Total number of polymer chains: 4
• Total formula weight: 170744.15

Authors

Stuckey, J.A.,Lawrence, D.A.,Li, S.-H. (deposition date: 2012-07-23, release date: 2013-12-25, Last modification date: 2024-02-28)

Primary citation

Li, S.H.,Reinke, A.A.,Sanders, K.L.,Emal, C.D.,Whisstock, J.C.,Stuckey, J.A.,Lawrence, D.A.
Mechanistic characterization and crystal structure of a small molecule inactivator bound to plasminogen activator inhibitor-1.
Proc.Natl.Acad.Sci.USA, 110:E4941-E4949, 2013

PubMed 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.

PubMed: 24297881
DOI: 10.1073/pnas.1216499110

Experimental method

X-RAY DIFFRACTION (2.71 Å)