Crystal structure of the Michaelis complex between tissue-type plasminogen activator and plasminogen activators inhibitor-1

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  • Lihu Gong, Chinese Academy of Sciences
  • ,
  • Min Liu, Chinese Academy of Sciences
  • ,
  • Tu Zeng, State 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
  • ,
  • Xiaoli Shi, State 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
  • ,
  • Cai Yuan, State 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
  • ,
  • Peter A. Andreasen, Centre for Carbohydrate Recognition and Signalling, Department of Molecular Biology and Genetics, Aarhus University
  • ,
  • Mingdong Huang, Chinese Academy of Sciences

Thrombosis is a leading cause of death worldwide. Recombinant tissue-type plasminogen activator (tPA) is the Food and Drug Administration-approved thrombolytic drug. tPA is rapidly inactivated by endogenous plasminogen activator inhibitor-1 (PAI-1). Engineering on tPA to reduce its inhibition by PAI-1 without compromising its thrombolytic effect is a continuous effort. Precise details, with atomic resolution, of the molecular interactions between tPA and PAI-1 remain unknown despite previous extensive studies. Here, we report the crystal structure of the tPA·;PAI-1 Michaelis complex, which shows significant differences from the structure of its urokinase-type plasminogen activator analogue, the uPA·;PAI-1 Michaelis complex. The PAI-1 reactive center loop adopts a unique kinked conformation. The structure provides detailed interactions between tPA 37- and 60-loops with PAI-1. On the tPA side, the S2 and S1β pockets open up to accommodate PAI-1. This study provides structural basis to understand the specificity of PAI-1 and to design newer generation of thrombolytic agents with reduced PAI-1 inactivation.

OriginalsprogEngelsk
TidsskriftJournal of Biological Chemistry
Vol/bind290
Nummer43
Sider (fra-til)25795-25804
Antal sider10
ISSN0021-9258
DOI
StatusUdgivet - 2015

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