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Structural insight into inactivation of plasminogen activator inhibitor-1 by a small-molecule antagonist.

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Structural insight into inactivation of plasminogen activator inhibitor-1 by a small-molecule antagonist. / Lin, Zhonghui; Jensen, Jan Kristian; Hong, Zebin; Shin, Xiaoli; Hu, Lihong; Andreasen, Peter; Huang, Mingdong.

I: Chemistry & Biology, Bind 20, Nr. 2, 21.02.2013, s. 253-261.

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avisTidsskriftartikelForskningpeer review

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Lin, Z, Jensen, JK, Hong, Z, Shin, X, Hu, L, Andreasen, P & Huang, M 2013, 'Structural insight into inactivation of plasminogen activator inhibitor-1 by a small-molecule antagonist.', Chemistry & Biology, bind 20, nr. 2, s. 253-261. https://doi.org/10.1016/j.chembiol.2013.01.002

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Author

Lin, Zhonghui ; Jensen, Jan Kristian ; Hong, Zebin ; Shin, Xiaoli ; Hu, Lihong ; Andreasen, Peter ; Huang, Mingdong. / Structural insight into inactivation of plasminogen activator inhibitor-1 by a small-molecule antagonist. I: Chemistry & Biology. 2013 ; Bind 20, Nr. 2. s. 253-261.

Bibtex

@article{63ac5ad1d04f4cf5be11c4d57e2a4363,
title = "Structural insight into inactivation of plasminogen activator inhibitor-1 by a small-molecule antagonist.",
abstract = "Plasminogen activator inhibitor-1 (PAI-1), a serpin, is the physiological inhibitor of tissue-type and urokinase-type plasminogen activators and thus also an inhibitor of fibrinolysis and tissue remodeling. It is a potential therapeutic target in many pathological conditions, including thrombosis and cancer. Several types of PAI-1 antagonist have been developed, but the structural basis for their action has remained largely unknown. Here we report X-ray crystal structure analysis of PAI-1 in complex with a small-molecule antagonist, embelin. We propose a mechanism for embelin-induced rapid conversion of PAI-1 into a substrate for its target proteases and the subsequent slow conversion of PAI-1 into an irreversibly inactivated form. Our work provides structural clues to an understanding of PAI-1 inactivation by small-molecule antagonists and an important step toward the design of drugs targeting PAI-1.",
author = "Zhonghui Lin and Jensen, {Jan Kristian} and Zebin Hong and Xiaoli Shin and Lihong Hu and Peter Andreasen and Mingdong Huang",
year = "2013",
month = feb,
day = "21",
doi = "10.1016/j.chembiol.2013.01.002",
language = "English",
volume = "20",
pages = "253--261",
journal = "Cell Chemical Biology",
issn = "2451-9456",
publisher = "Elsevier Inc.",
number = "2",

}

RIS

TY - JOUR

T1 - Structural insight into inactivation of plasminogen activator inhibitor-1 by a small-molecule antagonist.

AU - Lin, Zhonghui

AU - Jensen, Jan Kristian

AU - Hong, Zebin

AU - Shin, Xiaoli

AU - Hu, Lihong

AU - Andreasen, Peter

AU - Huang, Mingdong

PY - 2013/2/21

Y1 - 2013/2/21

N2 - Plasminogen activator inhibitor-1 (PAI-1), a serpin, is the physiological inhibitor of tissue-type and urokinase-type plasminogen activators and thus also an inhibitor of fibrinolysis and tissue remodeling. It is a potential therapeutic target in many pathological conditions, including thrombosis and cancer. Several types of PAI-1 antagonist have been developed, but the structural basis for their action has remained largely unknown. Here we report X-ray crystal structure analysis of PAI-1 in complex with a small-molecule antagonist, embelin. We propose a mechanism for embelin-induced rapid conversion of PAI-1 into a substrate for its target proteases and the subsequent slow conversion of PAI-1 into an irreversibly inactivated form. Our work provides structural clues to an understanding of PAI-1 inactivation by small-molecule antagonists and an important step toward the design of drugs targeting PAI-1.

AB - Plasminogen activator inhibitor-1 (PAI-1), a serpin, is the physiological inhibitor of tissue-type and urokinase-type plasminogen activators and thus also an inhibitor of fibrinolysis and tissue remodeling. It is a potential therapeutic target in many pathological conditions, including thrombosis and cancer. Several types of PAI-1 antagonist have been developed, but the structural basis for their action has remained largely unknown. Here we report X-ray crystal structure analysis of PAI-1 in complex with a small-molecule antagonist, embelin. We propose a mechanism for embelin-induced rapid conversion of PAI-1 into a substrate for its target proteases and the subsequent slow conversion of PAI-1 into an irreversibly inactivated form. Our work provides structural clues to an understanding of PAI-1 inactivation by small-molecule antagonists and an important step toward the design of drugs targeting PAI-1.

U2 - 10.1016/j.chembiol.2013.01.002

DO - 10.1016/j.chembiol.2013.01.002

M3 - Journal article

C2 - 23438754

VL - 20

SP - 253

EP - 261

JO - Cell Chemical Biology

JF - Cell Chemical Biology

SN - 2451-9456

IS - 2

ER -