4dva | pdb_00004dva

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

spinqualitylabelsall models 4dva, resolution 1.94Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4dva is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: P6G, SO4 Related: 2nwn, 4dvb, 4dw2 Gene: PLAU (HUMAN) Activity: U-plasminogen activator, with EC number 3.4.21.73 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease [UROK_HUMAN] Defects in PLAU are the cause of Quebec platelet disorder (QPD) [MIM:601709]. QPD is an autosomal dominant bleeding disorder due to a gain-of-function defect in fibrinolysis. Although affected individuals do not exhibit systemic fibrinolysis, they show delayed onset bleeding after challenge, such as surgery. The hallmark of the disorder is markedly increased PLAU levels within platelets, which causes intraplatelet plasmin generation and secondary degradation of alpha-granule proteins. Function [UROK_HUMAN] Specifically cleaves the zymogen plasminogen to form the active enzyme plasmin. Publication Abstract from PubMed 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. Rezymogenation of active urokinase induced by an inhibitory antibody.,Jiang L, Botkjaer KA, Andersen LM, Yuan C, Andreasen PA, Huang M Biochem J. 2013 Jan 1;449(1):161-6. doi: 10.1042/BJ20121132. PMID:23016918 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Urokinase

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