De novo design of alpha-amylase inhibitor: a small linear mimetic of macromolecular proteinaceous ligands
Jazyk angličtina Země Spojené státy americké Médium print
Typ dokumentu časopisecké články, práce podpořená grantem
PubMed
16356852
DOI
10.1016/j.chembiol.2005.10.005
PII: S1074-5521(05)00336-4
Knihovny.cz E-zdroje
- MeSH
- alfa-amylasy antagonisté a inhibitory chemie MeSH
- aminokyselinové motivy MeSH
- inhibitory enzymů chemie MeSH
- kinetika MeSH
- ligandy * MeSH
- molekulární mimikry * MeSH
- molekulární struktura MeSH
- peptidová knihovna * MeSH
- prasata MeSH
- vazebná místa MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- alfa-amylasy MeSH
- inhibitory enzymů MeSH
- ligandy * MeSH
- peptidová knihovna * 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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