Resisting degradation by human elastase: Commonality of design features shared by 'canonical' plant and bacterial macrocyclic protease inhibitor scaffolds

A previously unexplained difference in the resistance to enzymatic hydrolysis of 11-mer Bowman-Birk-type inhibitors of human leukocyte elastase that differ in PI is found to correlate with the strength of a particular intramolecular hydrogen bond within the inhibitor. This transarmular hydrogen bond stabilizes the side chain of the conserved P2 Thr in a 'canonical' +60 degrees-rotamer X, 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 scrine 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. (c) 2007 Elsevier Ltd. All rights reserved.