Structural basis of specific inhibition of tissue-type plasminogen activator by plasminogen activators inhibitor-1
Thrombosis is a leading cause of death worldwide [1]. Recombinant tissue-type plasminogen activator (tPA) is the FDA-approved thrombolytic drug for ischemic strokes, myocardial infarction and pulmonary embolism. tPA is a multi-domain serine protease of the trypsin-family [2] and catalyses the critic...
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doaj-547cac2abf08446fbe79d78256679deb2020-11-24T21:48:05ZengElsevierData in Brief2352-34092016-03-016550555Structural basis of specific inhibition of tissue-type plasminogen activator by plasminogen activators inhibitor-1Lihu Gong0Min Liu1Tu Zeng2Xiaoli Shi3Cai Yuan4Peter A. Andreasen5Mingdong Huang6State Key Laboratory of Structural Chemistry, Danish-Chinese Centre for Proteases and Cancer, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou, Fujian 350002, China; University of Chinese Academy of Sciences, Beijing 100049, ChinaState Key Laboratory of Structural Chemistry, Danish-Chinese Centre for Proteases and Cancer, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou, Fujian 350002, China; University of Chinese Academy of Sciences, Beijing 100049, ChinaState Key Laboratory of Structural Chemistry, Danish-Chinese Centre for Proteases and Cancer, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou, Fujian 350002, ChinaState Key Laboratory of Structural Chemistry, Danish-Chinese Centre for Proteases and Cancer, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou, Fujian 350002, ChinaState Key Laboratory of Structural Chemistry, Danish-Chinese Centre for Proteases and Cancer, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou, Fujian 350002, ChinaDanish-Chinese Centre for Proteases and Cancer, Department of Molecular Biology and Genetics, Aarhus University, 8000 Aarhus C, DenmarkState Key Laboratory of Structural Chemistry, Danish-Chinese Centre for Proteases and Cancer, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou, Fujian 350002, China; University of Chinese Academy of Sciences, Beijing 100049, China; Corresponding author.Thrombosis is a leading cause of death worldwide [1]. Recombinant tissue-type plasminogen activator (tPA) is the FDA-approved thrombolytic drug for ischemic strokes, myocardial infarction and pulmonary embolism. tPA is a multi-domain serine protease of the trypsin-family [2] and catalyses the critical step in fibrinolysis [3], converting the zymogen plasminogen to the active serine protease plasmin, which degrades the fibrin network of thrombi and blood clots. tPA is rapidly inactivated by endogenous plasminogen activators inhibitor-1 (PAI-1) [4] (Fig. 1). Engineering on tPA to reduce its inhibition by PAI-1 without compromising its thrombolytic effect is a continuous effort [5]. Tenecteplase (TNK-tPA) is a newer generation of tPA variant showing slower inhibition by PAI-1 [6]. Extensive studies to understand the molecular interactions between tPA and PAI-1 have been carried out [7–18], however, the precise details at atomic resolution remain unknown. We report the crystal structure of tPA·PAI-1 complex here. The methods required to achieve these data include: (1) recombinant expression and purification of a PAI-1 variant (14-1B) containing four mutations (N150H, K154T, Q319L, and M354I), and a tPA serine protease domain (tPA-SPD) variant with three mutations (C122A, N173Q, and S195A, in the chymotrypsin numbering) [19]; (2) formation of a tPA-SPD·PAI-1 Michaëlis complex in vitro [19]; and (3) solving the three-dimensional structure for this complex by X-ray crystallography [deposited in the PDB database as 5BRR]. The data explain the specificity of PAI-1 for tPA and uPA [19,20], and provide structural basis to design newer generation of PAI-1-resistant tPA variants as thrombolytic agents [19]. Keywords: Tpa, Serine protease, PAI-1, Serpin, Michaëlis complex, Crystal structure, Fibrinolysis, Thrombolytic agents, Structural biologyhttp://www.sciencedirect.com/science/article/pii/S2352340915004163 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Lihu Gong Min Liu Tu Zeng Xiaoli Shi Cai Yuan Peter A. Andreasen Mingdong Huang |
spellingShingle |
Lihu Gong Min Liu Tu Zeng Xiaoli Shi Cai Yuan Peter A. Andreasen Mingdong Huang Structural basis of specific inhibition of tissue-type plasminogen activator by plasminogen activators inhibitor-1 Data in Brief |
author_facet |
Lihu Gong Min Liu Tu Zeng Xiaoli Shi Cai Yuan Peter A. Andreasen Mingdong Huang |
author_sort |
Lihu Gong |
title |
Structural basis of specific inhibition of tissue-type plasminogen activator by plasminogen activators inhibitor-1 |
title_short |
Structural basis of specific inhibition of tissue-type plasminogen activator by plasminogen activators inhibitor-1 |
title_full |
Structural basis of specific inhibition of tissue-type plasminogen activator by plasminogen activators inhibitor-1 |
title_fullStr |
Structural basis of specific inhibition of tissue-type plasminogen activator by plasminogen activators inhibitor-1 |
title_full_unstemmed |
Structural basis of specific inhibition of tissue-type plasminogen activator by plasminogen activators inhibitor-1 |
title_sort |
structural basis of specific inhibition of tissue-type plasminogen activator by plasminogen activators inhibitor-1 |
publisher |
Elsevier |
series |
Data in Brief |
issn |
2352-3409 |
publishDate |
2016-03-01 |
description |
Thrombosis is a leading cause of death worldwide [1]. Recombinant tissue-type plasminogen activator (tPA) is the FDA-approved thrombolytic drug for ischemic strokes, myocardial infarction and pulmonary embolism. tPA is a multi-domain serine protease of the trypsin-family [2] and catalyses the critical step in fibrinolysis [3], converting the zymogen plasminogen to the active serine protease plasmin, which degrades the fibrin network of thrombi and blood clots. tPA is rapidly inactivated by endogenous plasminogen activators inhibitor-1 (PAI-1) [4] (Fig. 1). Engineering on tPA to reduce its inhibition by PAI-1 without compromising its thrombolytic effect is a continuous effort [5]. Tenecteplase (TNK-tPA) is a newer generation of tPA variant showing slower inhibition by PAI-1 [6]. Extensive studies to understand the molecular interactions between tPA and PAI-1 have been carried out [7–18], however, the precise details at atomic resolution remain unknown. We report the crystal structure of tPA·PAI-1 complex here. The methods required to achieve these data include: (1) recombinant expression and purification of a PAI-1 variant (14-1B) containing four mutations (N150H, K154T, Q319L, and M354I), and a tPA serine protease domain (tPA-SPD) variant with three mutations (C122A, N173Q, and S195A, in the chymotrypsin numbering) [19]; (2) formation of a tPA-SPD·PAI-1 Michaëlis complex in vitro [19]; and (3) solving the three-dimensional structure for this complex by X-ray crystallography [deposited in the PDB database as 5BRR]. The data explain the specificity of PAI-1 for tPA and uPA [19,20], and provide structural basis to design newer generation of PAI-1-resistant tPA variants as thrombolytic agents [19]. Keywords: Tpa, Serine protease, PAI-1, Serpin, Michaëlis complex, Crystal structure, Fibrinolysis, Thrombolytic agents, Structural biology |
url |
http://www.sciencedirect.com/science/article/pii/S2352340915004163 |
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