De novo design of alpha-amylase inhibitor: a small linear mimetic of macromolecular proteinaceous ligands
Language English Country United States Media print
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
16356852
DOI
10.1016/j.chembiol.2005.10.005
PII: S1074-5521(05)00336-4
Knihovny.cz E-resources
- MeSH
- alpha-Amylases antagonists & inhibitors chemistry MeSH
- Amino Acid Motifs MeSH
- Enzyme Inhibitors chemistry MeSH
- Kinetics MeSH
- Ligands * MeSH
- Molecular Mimicry * MeSH
- Molecular Structure MeSH
- Peptide Library * MeSH
- Swine MeSH
- Binding Sites MeSH
- Animals MeSH
- Check Tag
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- alpha-Amylases MeSH
- Enzyme Inhibitors MeSH
- Ligands * MeSH
- Peptide Library * MeSH
We report a low molecular weight inhibitor of alpha-amylases based on a linear peptidic scaffold designed de novo through the use of combinatorial chemistry. The inhibitory motif denoted PAMI (peptide amylase inhibitor) was selected by using L-peptide libraries and was fine-tuned by the introduction of unnatural modifications. PAMI specifically inhibits glycoside hydrolases of family 13. Its interaction with porcine pancreatic alpha-amylase was characterized by inhibition kinetics, fluorescence competition assays with natural alpha-amylase inhibitors, and isothermal titration calorimetry. We demonstrate that the critical amino acid residues in PAMI are shared with those in the macromolecular proteinaceous inhibitors that, however, bind to alpha-amylases through a spatially scattered set of intermolecular contacts. Thus, natural molecular evolution as well as combinatorial evolution selected the same alpha-amylase binding determinants for completely different spatial frameworks.
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