Tissue-type plasminogen activator: variants and crystal/solution structures demarcate structural determinants of function.
NMR and crystal structure of many components of tissue-type plasminogen activator (t-PA) are now available: the finger-EGF pair and the kringle-2 domain structures have been solved, as have the proteolytic domains of vampire bat PA and human t-PA in two- and single-chain forms. These structures confirm the trypsin-like arrangement of the proteolytic domain of t-PA and show how surface loops near the catalytic centre contribute to the narrow specificity of t-PA. Together with mutational experiments, they identify the Lys156 sidechain as a cause of the amidolytic activity of single-chain t-PA, as it can provide a substitute salt bridge partner for Asp194 in the absence of the Ile16 N terminus of the two-chain form. These new findings provide new ideas for the design of PA variants with improved therapeutic properties.
Bode
W
W
Max-Planck-Institut für Biochemie, Abteilung für Strukturforschung, Martinsried-Planegg, Germany. bode@biochem.mpg.de
Renatus
M
M
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D005337:Fibrin / Q000378:metabolism; D006801:Humans; D018082:Kringles; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011487:Protein Conformation; D013379:Substrate Specificity; D010959:Tissue Plasminogen Activator / Q000737:chemistry* / Q000378:metabolism
D004791:Enzyme Inhibitors; D005337:Fibrin; D010959:Tissue Plasminogen Activator