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 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.
Brauer
Arnd B E
AB
Department of Chemistry, Imperial College London, South Kensington Campus, London SW7 2AZ, UK. brauer@chemie.fu-berlin.de
McBride
Jeffrey D
JD
Kelly
Geoff
G
Matthews
Stephen J
SJ
Leatherbarrow
Robin J
RJ
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
D019151:Peptide Library; D011480:Protease Inhibitors; D010196:Pancreatic Elastase; D014357:Trypsin; D020860:Subtilisin