The structure of human microplasmin in complex with textilinin-1, an aprotinin-like inhibitor from the Australian brown snake.
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Millers EK, Johnson LA, Birrell GW, Masci PP, Lavin MF, de Jersey J, Guddat LW
The structure of human microplasmin in complex with textilinin-1, an aprotinin-like inhibitor from the Australian brown snake.
PLoS One. 2013;8(1):e54104. doi: 10.1371/journal.pone.0054104. Epub 2013 Jan 15.
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- 23335990 [ View in PubMed]
- Abstract
Textilinin-1 is a Kunitz-type serine protease inhibitor from Australian brown snake venom. Its ability to potently and specifically inhibit human plasmin (K(i) = 0.44 nM) makes it a potential therapeutic drug as a systemic anti-bleeding agent. The crystal structures of the human microplasmin-textilinin-1 and the trypsin-textilinin-1 complexes have been determined to 2.78 A and 1.64 A resolution respectively, and show that textilinin-1 binds to trypsin in a canonical mode but to microplasmin in an atypical mode with the catalytic histidine of microplasmin rotated out of the active site. The space vacated by the histidine side-chain in this complex is partially occupied by a water molecule. In the structure of microplasminogen the chi(1) dihedral angle of the side-chain of the catalytic histidine is rotated by 67 degrees from its "active" position in the catalytic triad, as exemplified by its location when microplasmin is bound to streptokinase. However, when textilinin-1 binds to microplasmin the chi(1) dihedral angle of this amino acid residue changes by -157 degrees (i.e. in the opposite rotation direction compared to microplasminogen). The unusual mode of interaction between textilinin-1 and plasmin explains textilinin-1's selectivity for human plasmin over plasma kallikrein. This difference can be exploited in future drug design efforts.