Amino Acid Scanning at P5′ within the Bowman–Birk Inhibitory Loop Reveals Specificity Trends for Diverse Serine Proteases
| Autor: | Simon J. de Veer, Choi Yi Li, Joakim E. Swedberg, Jonathan M. Harris, Xingchen Chen, David J. Craik, Andrew M. White |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
Proteases
Sequence (biology) Factor XIIa 01 natural sciences Substrate Specificity Serine 03 medical and health sciences Residue (chemistry) Drug Discovery medicine Chymotrypsin Humans Trypsin Amino Acids Trypsin Inhibitor Bowman-Birk Soybean 030304 developmental biology chemistry.chemical_classification 0303 health sciences Serine Endopeptidases Thrombin Cyclic peptide 0104 chemical sciences Amino acid 010404 medicinal & biomolecular chemistry Enzyme chemistry Biochemistry Molecular Medicine Serine Proteases medicine.drug |
| Zdroj: | Journal of Medicinal Chemistry. 62:3696-3706 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/acs.jmedchem.9b00211 |
| Popis: | Sunflower trypsin inhibitor-1 (SFTI-1) is a 14-amino acid cyclic peptide that shares an inhibitory loop with a sequence and structure similar to a larger family of serine protease inhibitors, the Bowman-Birk inhibitors. Here, we focus on the P5' residue in the Bowman-Birk inhibitory loop and produce a library of SFTI variants to characterize the P5' specificity of 11 different proteases. We identify seven amino acids that are generally preferred by these enzymes and also correlate with P5' sequence diversity in naturally occurring Bowman-Birk inhibitors. Additionally, we show that several enzymes have divergent specificities that can be harnessed in engineering studies. By optimizing the P5' residue, we improve the potency or selectivity of existing inhibitors for kallikrein-related peptidase 5 and show that a variant with substitutions at 7 of the scaffold's 14 residues retains a similar structure to SFTI-1. These findings provide new insights into P5' specificity requirements for the Bowman-Birk inhibitory loop. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|