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.
authors: State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou 350002, China.
authors: Zhonghui
authors: Z
authors: Lin
authors: Jan K
authors: JK
authors: Jensen
authors: Zebin
authors: Z
authors: Hong
authors: Xiaoli
authors: X
authors: Shi
authors: Lihong
authors: L
authors: Hu
authors: Peter A
authors: PA
authors: Andreasen
authors: Mingdong
authors: M
authors: Huang
mesh_terms: D016227:Benzoquinones / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D018360:Crystallography, X-Ray; D007700:Kinetics; D016297:Mutagenesis, Site-Directed; D017395:Plasminogen Activator Inhibitor 1 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000378:metabolism
chemical_list: D016227:Benzoquinones; D017395:Plasminogen Activator Inhibitor 1; D054852:Small Molecule Libraries; C010945:embelin