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

Millers, Emma-Karin I., Johnson, Lambro A., Birrell, Geoff W., Masci, Paul P., Lavin, Martin F., de Jersey, John and Guddat, Luke W. (2013) The structure of human microplasmin in complex with textilinin-1, an aprotinin-like inhibitor from the Australian brown snake. PLoS One, 8 1: e54104.1-e54104.12. doi:10.1371/journal.pone.0054104


Author Millers, Emma-Karin I.
Johnson, Lambro A.
Birrell, Geoff W.
Masci, Paul P.
Lavin, Martin F.
de Jersey, John
Guddat, Luke W.
Title The structure of human microplasmin in complex with textilinin-1, an aprotinin-like inhibitor from the Australian brown snake
Journal name PLoS One   Check publisher's open access policy
ISSN 1932-6203
Publication date 2013-01
Sub-type Article (original research)
DOI 10.1371/journal.pone.0054104
Open Access Status DOI
Volume 8
Issue 1
Start page e54104.1
End page e54104.12
Total pages 12
Place of publication San Francisco, CA, United States
Publisher Public Library of Science
Collection year 2014
Language eng
Abstract Textilinin-1 is a Kunitz-type serine protease inhibitor from Australian brown snake venom. Its ability to potently and specifically inhibit human plasmin (Ki = 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 χ1 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 χ1 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.
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ
Additional Notes Article # e54104

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2014 Collection
School of Chemistry and Molecular Biosciences
 
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Created: Fri, 25 Jan 2013, 13:51:16 EST by Mrs Louise Nimwegen on behalf of School of Chemistry & Molecular Biosciences