当前位置： SCI文献检索 > INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE期刊下所有文献 > Plasminogen activator inhibitor-1 is locked in active conformation and polymerizes upon binding ligands neutralizing its activity.

Plasminogen activator inhibitor-1 is locked in active conformation and polymerizes upon binding ligands neutralizing its activity.

Abstract：

:Plasminogen activator inhibitor-1 (PAI-1), a member of the serpin super-family, forms a covalent complex with its target proteinases, such as tissue and urokinase plasminogen activators. Thus, PAI-1 controls the physiological and pathological proteolysis. An abnormal expression of PAI-1 has been observed in different diseases, which can be treated by returning the proteolysis back to normal physiological levels. It has been reported that some PAI-1 inhibitors neutralize its activity by accelerating the conversion of PAI-1 into a latent form. We have found small organic chemicals that also neutralize PAI-1 activity, but by a different mechanism. Using the NBD fluorescent probe [N,N'-dimethyl-N-(acetyl)-N'-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)] incorporated into the reactive center loop (RCL) of PAI-1, we measured the kinetics of conversion from an active to a latent form. Unexpectedly, we found that some inhibitors of PAI-1 arrest this serpin in its active form instead of increasing the speed of conversion. Using docking calculations, we located two possible binding sites for these chemicals. The sites are in proximity of the P1/P1' amino acids of the RCL of PAI-1. Binding in this area can inactivate PAI-1 and additionally create a steric obstacle on the RCL making insertion of this loop between the A3 and A5 strands more difficult; hence abolishing a necessary step in the conversion of this protein into the latent form. Additionally, PAI-1 inhibitors link the RCL of one PAI-1 molecule with the strand 3C and strand 4C or helix A and strand 1B regions of the other PAI-1 molecule aiding polymerization or stabilizing the junction of the two. The polymerization of PAI-1 reduces PAI-1 activity by encapsulating the critical RCL fragment inside the formed PAI-1/PAI-1 polymers.

journal_name

Int J Mol Med

journal_title

International journal of molecular medicine

authors

Jankun J,Specht Z,Szkudlarek M,Greenfield R,Gaikwad B,Trifonov L,Vaugeois J,Aleem AM,Basrur V,Selman SH,Zavodszky MI,Skrzypczak-Jankun E

subject

Has Abstract

pub_date

2006-03-01 00:00:00

pages

437-47

issue

eissn

1107-3756

issn

1791-244X

journal_volume

pub_type

杂志文章

在线工具

Plasminogen activator inhibitor-1 is locked in active conformation and polymerizes upon binding ligands neutralizing its activity.