Mechanisms of Macromolecular Protease Inhibitors

Graduate Group in Biophysics, University of California-San Francisco, San Francisco, CA 94143-2240, USA.
ChemBioChem (Impact Factor: 3.09). 11/2010; 11(17):2341-6. DOI: 10.1002/cbic.201000442
Source: PubMed


Relatively few design principles underlie the inhibition mechanisms of macromolecular protease inhibitors. These inhibitors tend to compete with substrate binding either through direct competition or deformation of the protease active site; they gain potency and specificity by burying a large surface area and through contacts with specific exosites. Protein engineering has allowed both potency and specificity to be modified.

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Available from: Charles S Craik,
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    • "Although the majority of cysteine protease inhibitors binds into the active site and blocks the access to their target protease, they do not bind in a strictly substrate-like manner (Laskowski & Kato, 1980; Farady & Craik, 2010). Instead, they interact with the cysteine protease subsites and catalytic residues in a non-catalytically competent manner (Farady & Craik, 2010). This view is based upon the observation that static Xray cysteine proteases structures, several in free form and complexed to inhibitors (mainly covalent inhibitors), show little differences in their conformation, as measured by the deviation of backbone dihedral angles (Laskowski & Qasim, 2000; Ratia et al., 2008; Gaspari, Varnai, Szappanos & Perczel, 2010). "
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    Journal of biomolecular Structure & Dynamics 09/2015; DOI:10.1080/07391102.2015.1100139 · 2.92 Impact Factor
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    • "Recently, the Kunitz-type serine protease inhibitor HAI-2 (hepatocyte growth factor activator inhibitor type 2) has been shown to inhibit the proteolytic activity of MT-2 [9]. Since Kunitz-type inhibitors bind to their target proteases in a substrate-like manner [10], HAI-2 can also be considered to bear a processing site attacked by MT-2. For instance, Kunitz domain I exhibited two critical Arg residues which might be recognized by MT-2. "
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    Biochimie 10/2013; 97(1). DOI:10.1016/j.biochi.2013.10.001 · 2.96 Impact Factor
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    • "Considering eleven mammalian species (Figure 3), methionine is always present at this position except in mouse. Moreover methionine in this position (P1 position of RCL region) has been demonstrated to be involved in the interaction of AAT with its substrates, the proteases [26,27]. Different phylogeny studies of the serpin superfamily showed the importance of the amino acid composition of the RCL region to determine the ability to bind protease and non protease ligand [1,28]. "
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