Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.73 (urokinase-type plasminogen activator)
 10,685 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Serpins inhibit serine proteinases through formation of stable 1:1 complexes. In this study we have evaluated the effects of PAI-1 neutralizing antibodies (MA) on the stability of PAI-1/proteinase complexes, partially destabilized through prolongation of the reactive center loop. MA-8H9D4, reacting with residues Arg(300), Gln(303), and Asp(305), had no effect on the stability. In contrast, MA-33H1F7 and MA-55F4C12, reacting with alpha-helix F and the turn connecting hF with s3A, affected significantly and proteinase-dependently formed PAI-1/proteinase complexes. That is, MA-33H1F7 increased the stability of both PAI-1/t-PA and u-PA complexes (7- and 3-fold, respectively) whereas MA-55F4C12 stabilized PAI-1/t-PA complexes (3-fold) but destabilized PAI-1/u-PA complexes (2-fold). It is concluded that interference with the docking site of the cognate proteinase in the preformed serpin/proteinase complex may affect the intrinsic stability. We hypothesize that this is the consequence of a decreased or increased torsion of the RCL on the catalytic triad in the proteinase.
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PMID:Structural determinants in the stability of the serpin/proteinase complex. 1289 54

PAI-1 is a Mr ~50,000 glycoprotein, which is the primary physiological inhibitor of the two plasminogen activators uPA and tPA. PAI-1 belongs to the serpin protein family. Studies of PAI-1 have contributed significantly to the elucidation of the protease inhibitory mechanism of serpins, which is based on a metastable native state becoming stabilised by insertion of the RCL into the central beta-sheet A and formation of covalent complexes with target proteases. In PAI-1, this insertion can occur in the absence of the protease, resulting in generation of a so-called latent, inactive form of the protein. PAI-1, in its active state, also binds to the extracellular protein vitronectin. When in complex with its target proteases, it binds with high affinity to endocytosis receptors of the low density receptor family.
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PMID:Biochemical properties of plasminogen activator inhibitor-1. 1927 34