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Knowledge-based modeling of the serine protease triad into non-proteases

Iengar, Prathima and Ramakrishnan, C (1999) Knowledge-based modeling of the serine protease triad into non-proteases. In: Protein Engineering, 12 (8). pp. 649-655.

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The Asp–His–Ser triad of serine proteases has been regarded, in the present study, as an independent catalytic motif, because in nature it has been incorporated at the active sites of enzymes as diverse as the serine proteases and the lipases. Incorporating this motif into non-protease scaffolds, by rational design and mutagenesis, might lead to the generation of novel catalysts. As an aid to such experiments, a knowledge-based computer modeling procedure has been developed to model the protease Asp–His–Ser triad into non-proteases. Catalytic triads from a set of trypsin family proteases have been analyzed and criteria that characterize the geometry of the triads have been obtained. Using these criteria, the modeling procedure first identifies sites in non-proteases that are suitable for modeling the protease triad. H-bonded Asp–His–Ser triads, that mimic the protease catalytic triad in geometry, are then modeled in at these sites, provided it is stereochemically possible to do so. Thus non-protease sites at which H-bonded Asp–His–Ser triads are successfully modeled in may be considered for mutagenesis experiments that aim at introducing the protease triad into non-proteases. The triad modeling procedure has been used to identify sites for introducing the protease triad in three binding proteins and an immunoglobulin. A scoring function, depending on inter-residue distances, solvent accessibility and the substitution potential of amino acid residues at the modeling sites in the host proteins, has been used to assess the quality of the model triads

Item Type: Journal Article
Publication: Protein Engineering
Publisher: Oxford University Press
Additional Information: copyright of this article belongs to Oxford University Press
Keywords: catalytic triad;knowledge based modeling;serine protease;triad modeling procedure
Department/Centre: Division of Biological Sciences > Molecular Biophysics Unit
Date Deposited: 10 Oct 2007
Last Modified: 19 Sep 2010 04:40
URI: http://eprints.iisc.ac.in/id/eprint/12203

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