PDBsum entry 4dva

Hydrolase

PDB id: 4dva

Contents

Protein chain

246 a.a.

Ligands

SO4 ×2

P6G ×2

Waters ×175

PDB id:

4dva

Name:

Hydrolase

Title:

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

Structure:

Urokinase-type plasminogen activator. Chain: u. Fragment: catalytic domain. Synonym: u-plasminogen activator, upa. Engineered: yes. Mutation: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: plau. Expressed in: pichia pastoris. Expression_system_taxid: 4922.

Resolution:

1.94Å R-factor: 0.200 R-free: 0.244

Authors:

L.Jiang,K.A.Botkjaer,L.M.Andersen,C.Yuan,P.A.Andreasen,M.Huang

Key ref:

L.Jiang et al. (2013). Rezymogenation of active urokinase induced by an inhibitory antibody. Biochem J, 449, 161-166. PubMed id: 23016918

Date:

23-Feb-12 Release date: 16-Jan-13

Protein chain

P00749  (UROK_HUMAN) -  Urokinase-type plasminogen activator from Homo sapiens

Seq: 431 a.a.

Struc: 246 a.a.*

* PDB and UniProt seqs differ at 2 residue positions (black crosses)

Enzyme reactions

• Enzyme class: E.C.3.4.21.73 - u-plasminogen activator.
• Reaction: Specific cleavage of Arg-|-Val bond in plasminogen to form plasmin.

Biochem J 449:161-166 (2013)

PubMed id: 23016918

Rezymogenation of active urokinase induced by an inhibitory antibody.

L.Jiang, K.A.Botkjaer, L.M.Andersen, C.Yuan, P.A.Andreasen, M.Huang.

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.