5BRR: Michaelis Complex Of Tpa-s195a:pai-1

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 S1beta 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.
PDB ID: 5BRRDownload
MMDB ID: 132316
PDB Deposition Date: 2015/6/1
Updated in MMDB: 2015/11
Experimental Method:
x-ray diffraction
Resolution: 3.16  Å
Source Organism:
Similar Structures:
Biological Unit for 5BRR: dimeric; determined by author and by software (PISA)
Molecular Components in 5BRR
Label Count Molecule
Proteins (2 molecules)
Plasminogen Activator Inhibitor 1(Gene symbol: SERPINE1)
Molecule annotation
Tissue-type Plasminogen Activator(Gene symbol: PLAT)
Molecule annotation
Chemicals (5 molecules)
* Click molecule labels to explore molecular sequence information.

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