Resisting degradation by human elastase: Commonality of design features shared by ‘canonical’ plant and bacterial macrocyclic protease inhibitor scaffolds
- 作者：Arnd B.E. Brauer ; Jeffrey D. McBride ; Geoff Kelly ; Stephen J. Matthews ; Robin J. Leatherbarrow
- 关键词：P2 threonine ; Human elastase ; Bowman– ; Birk serine protease inhibitor ; Depsipeptides
- 刊名：Bioorganic and Medicinal Chemistry
- 出版年：2007
- 期刊代码：9_09680896
- 类别：ch
- 出版时间：1 July 2007
- 卷：15
- 期：13
- 页码：4618-4628
- 文件大小：669 K
摘要
A previously unexplained difference in the resistance to enzymatic hydrolysis of 11-mer Bowman–Birk-type inhibitors of human leukocyte elastase that differ in P1 is found to correlate with the strength of a particular intramolecular hydrogen bond within the inhibitor. This transannular hydrogen bond stabilizes the side chain of the conserved P2 Thr in a ‘canonical’ +60°-rotamer χ1 conformation and thereby directs it for a close interaction with the enzyme’s catalytic His. As the implications of this NMR analysis are neither limited to this macrocyclic scaffold derived from plant proteins nor to a particular serine protease, we present a unified analysis with inhibitory bacterial depsipeptides of 7–12 residues in length that share key design features for which we propose communal functional explanations.