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Title

Towards Tricking a Pathogen's Protease into Fighting Infection: The 3D Structure of a Stable Circularly Permuted Onconase Variant Cleavedby HIV-1 Protease

AuthorsCallís, Mariona; Serrano, Soraya; Benito, Antoni; Laurents, D.V. ; Vilanova, M.; Bruix, M. ; Ribó, Marc
Issue Date2013
PublisherPublic Library of Science
CitationPLoS ONE 8 (2013)
AbstractOnconase® is a highly cytotoxic amphibian homolog of Ribonuclease A. Here, we describe the construction of circularly permuted Onconase® variants by connecting the N- and C-termini of this enzyme with amino acid residues that are recognized and cleaved by the human immunodeficiency virus protease. Uncleaved circularly permuted Onconase® variants are unusually stable, non-cytotoxic and can internalize in human T-lymphocyte Jurkat cells. The structure, stability and dynamics of an intact and a cleaved circularly permuted Onconase® variant were determined by Nuclear Magnetic Resonance spectroscopy and provide valuable insight into the changes in catalytic efficiency caused by the cleavage. The understanding of the structural environment and the dynamics of the activation process represents a first step toward the development of more effective drugs for the treatment of diseases related to pathogens expressing a specific protease. By taking advantage of the protease's activity to initiate a cytotoxic cascade, this approach is thought to be less susceptible to known resistance mechanisms.
URIhttp://hdl.handle.net/10261/67431
DOI10.1371/journal.pone.0054568
Identifiersdoi: 10.1371/journal.pone.0054568
issn: 1932-6203
Appears in Collections:(IQFR) Artículos
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