Skip to main content

A protease inhibitor as a potential therapeutic target in cancer: Conversion of plasminogen activator inhibitor-1 to an inactive latent state can be accelerated by a peptide or an antibody binding to the

α-helix D-β-strand 2A loop

Buy Article:

$51.00 plus tax (Refund Policy)


The serpin plasminogen activator inhibitor-1 (PAI-1) is a specific inhibitor of the plasminogen activators and a potential therapeutic target in cancer. Accordingly, formation of a basis for development of specific PAI-1 inactivating agents is of great interest. One possible inactivation mode for PAI-1 is conversion to the inactive, so-called latent state. We have now screened a phage-displayed peptide library with PAI-1 as bait and isolated a 31-residue cysteine-rich peptide which will be referred to as paionin-4. A recombinant protein consisting of paionin-4 fused to domains 1 and 2 of the phage coat protein g3p caused a 2 – 3 fold increase in the rate of spontaneous inactivation of PAI-1. Paionin-4 bound PAI-1 with a KD in the nM range. Using several biochemical and biophysical methods, we demonstrate that paionin-4-stimulated inactivation consists in an acceleration of conversion to the latent state. As demonstrated by site-directed mutagenesis and competition with other PAI-1 ligands, the binding site for paionin-4 was localized in the loop between α-helix D and â-strand 2A. We also demonstrate that a latency-inducing monoclonal antibody has an overlapping, but not identical binding site, and accelerates latency transition by another mechanism. Our results show that paionin-4 inactivates PAI-1 by a mechanism clearly different from other peptides, small organochemical compounds, or antibodies, whether they cause inactivation by stimulating latency transition or by other mechanisms, and that the loop between α-helix D and â-strand 2A can be a target for PAI-1 inactivation by different types of compounds.

Document Type: Abstract


Publication date: May 1, 2008


Access Key

Free Content
Free content
New Content
New content
Open Access Content
Open access content
Subscribed Content
Subscribed content
Free Trial Content
Free trial content
Cookie Policy
Cookie Policy
Ingenta Connect website makes use of cookies so as to keep track of data that you have filled in. I am Happy with this Find out more