Subtle structural differences between human and mouse PAI-1 reveal the basis for biochemical differences.

Abstract:

:Plasminogen activator inhibitor-1 (PAI-1) is a serine protease inhibitor (serpin) that plays an important role in cardiovascular disorders and tumor development. The potential role of PAI-1 as a drug target has been evaluated in various animal models (e.g. mouse and rat). Sensitivity to PAI-1 inhibitory agents varied in different species. To date, absence of PAI-1 structures from species other than human hampers efforts to reveal the molecular basis for the observed species differences. Here we describe the structure of latent mouse PAI-1. Comparison with available structures of human PAI-1 reveals (1) a differential positioning of α-helix A; (2) differences in the gate region; and (3) differences in the reactive center loop position. We demonstrate that the optimal binding site of inhibitors may be dependent on the orthologs, and our results affect strategies in the rational design of a pharmacologically active PAI-1 inhibitor.

journal_name

J Struct Biol

authors

Dewilde M,Van De Craen B,Compernolle G,Madsen JB,Strelkov S,Gils A,Declerck PJ

doi

10.1016/j.jsb.2010.03.006

subject

Has Abstract

pub_date

2010-07-01 00:00:00

pages

95-101

issue

1

eissn

1047-8477

issn

1095-8657

pii

S1047-8477(10)00083-3

journal_volume

171

pub_type

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