4DVA

The crystal structure of human urokinase-type plasminogen activator catalytic domain

Summary for 4DVA

• Entry DOI: 10.2210/pdb4dva/pdb
• Related: 2NWN 4DVB 4DW2
• Descriptor: Urokinase-type plasminogen activator, SULFATE ION, HEXAETHYLENE GLYCOL, ... (4 entities in total)
• Functional Keywords: hydrolase, plasminogen activation, protease, serine protease
• Biological source: Homo sapiens (human)
• Cellular location: Secreted: P00749
• Total number of polymer chains: 1
• Total formula weight: 28472.39

Authors

Jiang, L.,Botkjaer, K.A.,Andersen, L.M.,Yuan, C.,Andreasen, P.A.,Huang, M. (deposition date: 2012-02-23, release date: 2013-01-16, Last modification date: 2024-11-20)

Primary citation

Jiang, L.,Botkjaer, K.A.,Andersen, L.M.,Yuan, C.,Andreasen, P.A.,Huang, M.
Rezymogenation of active urokinase induced by an inhibitory antibody
Biochem.J., 449:161-166, 2013

PubMed Abstract: An important regulatory mechanism of serine proteases is the proteolytic conversion of the inactive pro-enzyme, or zymogen, into the active enzyme. This activation process is generally considered an irreversible process. In the present study, we demonstrate that an active enzyme can be converted back into its zymogen form. We determined the crystal structure of uPA (urokinase-type plasminogen activator) in complex with an inhibitory antibody, revealing that the antibody 'rezymogenizes' already activated uPA. The present study demonstrates a new regulatory mechanism of protease activity, which is also an extreme case of protein allostery. Mechanistically, the antibody binds a single surface-exposed loop, named the autolysis loop, thereby preventing the stabilization of uPA in its active conformation. We argue that this autolysis loop is a key structural element for rezymogenation of other proteases, and will be a new target site for pharmacological intervention with serine protease activity.

PubMed: 23016918
DOI: 10.1042/BJ20121132

Experimental method

X-RAY DIFFRACTION (1.94 Å)