Mechanism of inactivation of plasminogen activator inhibitor-1 by a small molecule inhibitor.

Mechanism of inactivation of plasminogen activator inhibitor-1 by a small molecule inhibitor. Research Abstract Details 

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Mechanism of inactivation of plasminogen activator inhibitor-1 by a small molecule inhibitor. Abstract Text:

Natalia V Gorlatova,Jacqueline M Cale,Hassan Elokdah,Donghua Li,Kristi Fan,Mark Warnock,David L Crandall,Daniel A Lawrence,

The inactivation of plasminogen activator inhibitor-1 (PAI-1) by the small molecule PAI-1 inhibitor PAI-039 (tiplaxtinin) has been investigated using enzymatic analysis, direct binding studies, site-directed mutagenesis, and molecular modeling studies. Previously PAI-039 has been shown to exhibit in vivo activity in various animal models, but the mechanism of inhibition is unknown. PAI-039 bound specifically to the active conformation of PAI-1 and exhibited reversible inactivation of PAI-1 in vitro. SDS-PAGE indicated that PAI-039 inactivated PAI-1 predominantly through induction of PAI-1 substrate behavior. Preincubation of PAI-1 with vitronectin, but not bovine serum albumin, blocked PAI-039 activity while analysis of the reciprocal experiment demonstrated that preincubation of PAI-1 with PAI-039 blocked the binding of PAI-1 to vitronectin. Together, these data suggest that the site of interaction of the drug on PAI-1 is inaccessible when PAI-1 is bound to vitronectin and may overlap with the PAI-1 vitronectin binding domain. This was confirmed by site-directed mutagenesis and molecular modeling studies, which suggest that the binding epitope for PAI-039 is localized adjacent to the previously identified interaction site for vitronectin. Thus, these studies provide a detailed characterization of the mechanism of inhibition of PAI-1 by PAI-039 against free, but not vitronectin-bound PAI-1, suggesting for the first time a novel pool of PAI-1 exists that is vulnerable to inhibition by inactivators that bind at the vitronectin binding site.

Mechanism of inactivation of plasminogen activator inhibitor-1 by a small molecule inhibitor. Publishing Authors By Initials

NV Gorlatova,JM Cale,H Elokdah,D Li,K Fan,M Warnock,DL Crandall,DA Lawrence,

For similar proteins: blood proteins: vitronectin research abstracts see: proteins: blood proteins: vitronectin research

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Mechanism of inactivation of plasminogen activator inhibitor-1 by a small molecule inhibitor. Journal Published:

PUBLICATION TYPE: Research Support, Non-U.S. Gov

Journal: The Journal of biological chemistry

VOLUME: 282

Page Numbers: 9288-96

Journal Abbreviation: J. Biol. Chem.

ISSN: 0021-9258

DAY: 2

MONTH: 02

YEAR: 2007

Mechanism of inactivation of plasminogen activator inhibitor-1 by a small molecule inhibitor. Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 2985121

Mechanism of inactivation of plasminogen activator inhibitor-1 by a small molecule inhibitor. Keywords Mesh Terms:

KEYWORDS: Vitronectin

MESH TERMS: chemistry

Chemical & Substance for Abstract: Mechanism of inactivation of plasminogen activator inhibitor-1 by a small molecule inhibitor. Information

Substance Name: tiplaxtinin

Registry Number: 0

Grant and Affiliation Information for Mechanism of inactivation of plasminogen activator inhibitor-1 by a small molecule inhibitor.

AFFILIATION: Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan 48109-0644, USA.

Country: United States

AGENCY: United States NHLBI

GRANT: P01HL54710

ACRONYM: HL

MEDLINETA: J Biol Chem

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