title: 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: School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Queensland, Australia.
authors: Emma-Karin I
authors: EK
authors: Millers
authors: Lambro A
authors: LA
authors: Johnson
authors: Geoff W
authors: GW
authors: Birrell
authors: Paul P
authors: PP
authors: Masci
authors: Martin F
authors: MF
authors: Lavin
authors: John
authors: J
authors: de Jersey
authors: Luke W
authors: LW
authors: Guddat
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D007611:Aprotinin / Q000494:pharmacology; D018360:Crystallography, X-Ray; D004546:Elapid Venoms / Q000737:chemistry* / Q000494:pharmacology; D005341:Fibrinolysin / Q000032:analysis / Q000037:antagonists & inhibitors / Q000737:chemistry*; D006801:Humans; D046911:Macromolecular Substances / Q000737:chemistry*; D062105:Molecular Docking Simulation; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000737:chemistry*; D020842:Plasma Kallikrein / Q000037:antagonists & inhibitors; D011485:Protein Binding; D011487:Protein Conformation; D016415:Sequence Alignment; D012910:Snake Venoms / Q000737:chemistry* / Q000494:pharmacology; D014357:Trypsin / Q000737:chemistry / Q000378:metabolism
chemical_list: D004546:Elapid Venoms; D046911:Macromolecular Substances; D010446:Peptide Fragments; D012910:Snake Venoms; C413544:textilinin; C054561:microplasmin; D007611:Aprotinin; D020842:Plasma Kallikrein; D014357:Trypsin; D005341:Fibrinolysin