The structure of human microplasmin in complex with textilinin-1, an aprotinin-like inhibitor from the Australian brown snake.

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 Å and 1.64 Å 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 χ(1) dihedral angle of the side-chain of the catalytic histidine is rotated by 67° 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 χ(1) dihedral angle of this amino acid residue changes by -157° (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.

• Authors: Emma-Karin I Millers, Lambro A Johnson, Geoff W Birrell, Paul P Masci, Martin F Lavin, John de Jersey, Luke W Guddat
• Journal: PloS one (PLoS One) Vol. 8 Issue 1 Pg. e54104 ( 2013) ISSN: 1932-6203 [Electronic] United States
• PMID: 23335990 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Elapid Venoms
• Macromolecular Substances
• Peptide Fragments
• Snake Venoms
• textilinin
• microplasmin
• Aprotinin
• Plasma Kallikrein
• Trypsin
• Fibrinolysin

Topics

• Amino Acid Sequence
• Animals
• Aprotinin (pharmacology)
• Crystallography, X-Ray
• Elapid Venoms (chemistry, pharmacology)
• Fibrinolysin (analysis, antagonists & inhibitors, chemistry)
• Humans
• Macromolecular Substances (chemistry)
• Molecular Docking Simulation
• Molecular Sequence Data
• Peptide Fragments (antagonists & inhibitors, chemistry)
• Plasma Kallikrein (antagonists & inhibitors)
• Protein Binding
• Protein Conformation
• Sequence Alignment
• Snake Venoms (chemistry, pharmacology)
• Trypsin (chemistry, metabolism)