TISSUE-TYPE PLASMINOGEN-ACTIVATOR - VARIANTS AND CRYSTAL SOLUTION STRUCTURES DEMARCATE STRUCTURAL DETERMINANTS OF FUNCTION/

NMR and crystal structures of many components of tissue-type plasminog en activator (t-PA) are now available: the finger-EGF pair and the kri ngle-2 domain structures have been solved, as have the proteolytic dom ains of vampire bat PA and human t-PA in two-and single-chain forms. T hese structures confirm the trypsin-like arrangement of the proteolyti c domain of t-PA and show how surface loops near the catalytic centre contribute to the narrow specificity of PPA. Together with mutational experiments, they identify the Lys156 sidechain as a cause of the amid olytic activity of single-chain t-PA, as it can provide a substitute s alt bridge partner for Asp194 in the absence of the Ile16 N terminus o f the two-chain form. These new findings provide new ideas for the des ign of PA variants with improved therapeutic properties. (C) Current B iology Ltd ISSN 0959-440X.