Document Detail

Novel protease inhibitors via computational redesign of subtilisin BPN' propeptide.
MedLine Citation:
PMID:  23009354     Owner:  NLM     Status:  Publisher    
The propeptide domain of subtilisin BPN' functions as a molecular chaperone for its cognate protease, yet quickly assumes a predominantly unfolded structure following cleavage by the mature protease. In contrast, structural stabilization of the propeptide domain has been proposed to competitively inhibit protease self-cleavage, suggesting the possibility for the generation of novel proteinacious subtilisin inhibitors. Using Rosetta fixed backbone design, we have redesigned the subtilisin BPN' propeptide structure to generate synthetic peptide sequences with increased and tunable structural stability. Molecular dynamics simulations provide supporting evidence that the artificial sequences retain structure without its protease cognate unlike the inherently disordered wild type propeptide. Experimental evaluation of two designer domains by spectroscopic methods verified their structural integrity. Furthermore, the novel propeptide domains were shown to possess significantly enhanced thermostability. Nevertheless, their modest functional performance as protease inhibitors raises doubt that propeptide stability alone is sufficient for effective inhibitor design.
Ashley B Daugherty; Pravin Muthu; Stefan Lutz
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-9-25
Journal Detail:
Title:  Biochemistry     Volume:  -     ISSN:  1520-4995     ISO Abbreviation:  Biochemistry     Publication Date:  2012 Sep 
Date Detail:
Created Date:  2012-9-26     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0370623     Medline TA:  Biochemistry     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
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