5BRR

Michaelis complex of tPA-S195A:PAI-1

Summary for 5BRR

• Entry DOI: 10.2210/pdb5brr/pdb
• Descriptor: Plasminogen activator inhibitor 1, Tissue-type plasminogen activator, GLYCEROL, ... (5 entities in total)
• Functional Keywords: tissue-type plasminogen activator catalytic domain, plasminogen activator inhibitor 1, structure-activity relationship, thrombolysis, hydrolase inhibitor-hydrolase complex, hydrolase inhibitor/hydrolase
• Biological source: Homo sapiens (Human); More
• Cellular location: Secreted: P05121; Secreted, extracellular space: P00750
• Total number of polymer chains: 2
• Total formula weight: 71424.42

Authors

Gong, L. (deposition date: 2015-06-01, release date: 2015-09-02, Last modification date: 2024-11-20)

Primary citation

Gong, L.,Liu, M.,Zeng, T.,Shi, X.,Yuan, C.,Andreasen, P.A.,Huang, M.
Crystal Structure of the Michaelis Complex between Tissue-type Plasminogen Activator and Plasminogen Activators Inhibitor-1
J.Biol.Chem., 290:25795-25804, 2015

PubMed Abstract: 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.

PubMed: 26324706
DOI: 10.1074/jbc.M115.677567

Experimental method

X-RAY DIFFRACTION (3.16 Å)