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

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  • Zhonghui Lin, State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Kina
  • Jan Kristian Jensen
  • Zebin Hong, Kina
  • Xiaoli Shin, State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Kina
  • Lihong Hu, State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Kina
  • Peter Andreasen, Danmark
  • Mingdong Huang, State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou, China, Kina
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.
OriginalsprogEngelsk
TidsskriftChemistry & Biology
Vol/bind20
Nummer2
Sider (fra-til)253-261
Antal sider9
ISSN1074-5521
DOI
StatusUdgivet - 21 feb. 2013

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