Adaptation of plasminogen activator sequences to known protease structures

• Published in: FEBS letters 1983-07, Vol.157 (2), p.219-223
• Main Authors: Straßburger, W., Wollmer, A., Pitts, J.E., Glover, I.D., Tickle, I.J., Blundell, T.L., Steffens, G.J., Günzler, W.A., Ötting, F., Flohé, L.
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Chymotrypsin; Chymotrypsin - analysis; Computer graphics; elastase; Endopeptidases - analysis; high molecular mass urokinase; HUK; Humans; low molecular mass urokinase; LUK; Model building; Pancreatic Elastase - analysis; pancreatic trypsin inhibitor; Peptide Hydrolases - analysis; Plasminogen Activators - analysis; Protein Conformation; PTI; SCR; Sequence alignment; structurally conserved region; Structure-Activity Relationship; tissue plasminogen activating enzyme; Tissue-type plasminogen activator; TPA; Trypsin; Trypsin - analysis; Urokinase; Urokinase-Type Plasminogen Activator - analysis; β-Structure formation
• ISSN: 0014-5793; 1873-3468
• DOI: 10.1016/0014-5793(83)80551-1

The sequences of urokinase (UK) and tissue-type plasminogen activator (TPA) were aligned with those of chymotrypsin, trypsin, and elastase according to their ‘structurally conserved regions’. In spite of its trypsin-like specificity UK was model-built on the basis of the chymotrypsin structure because of a corresponding disulfide pattern. The extra disulfide bond falls to cysteines 50 and 111d. Insertions can easily be accommodated at the surface. As they occur similarly in both, UK and TPA, a role in plasminogen recognition may be possible. Of the functional positions known to be involved in substrate or inhibitor binding, Asp 97, Lys 143 and Arg 217 (Leu in TPA) may contribute to plasminogen activating specificity. PTI binding may in part be impaired by structural differences at the edge of the binding pocket.