title: Resisting degradation by human elastase: commonality of design features shared by 'canonical' plant and bacterial macrocyclic protease inhibitor scaffolds.
abstract: 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 degrees -rotamer chi(1) 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.
authors.affiliation: Department of Chemistry, Imperial College London, South Kensington Campus, London SW7 2AZ, UK. brauer@chemie.fu-berlin.de
authors.forename: Arnd B E
authors.initials: AB
authors.lastname: Brauer
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: McBride
authors.forename: Geoff
authors.initials: G
authors.lastname: Kelly
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Matthews
authors.forename: Robin J
authors.initials: RJ
authors.lastname: Leatherbarrow
mesh_terms: D015195:Drug Design; D006801:Humans; D006860:Hydrogen Bonding; D006868:Hydrolysis; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D010196:Pancreatic Elastase / Q000378:metabolism*; D019151:Peptide Library; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D021281:Quantitative Structure-Activity Relationship; D020860:Subtilisin / Q000737:chemistry; D014357:Trypsin / Q000737:chemistry
chemical_list: D019151:Peptide Library; D011480:Protease Inhibitors; D010196:Pancreatic Elastase; D014357:Trypsin; D020860:Subtilisin