title: A mechanistic study on the inhibition of α-chymotrypsin by a macrocyclic peptidomimetic aldehyde.
abstract: Here we describe an NMR and X-ray crystallography-based characterisation of the mechanism by which a new class of macrocyclic peptidomimetic aldehyde inhibits α-chymotrypsin. In particular, a (13)C-labelled analogue of the inhibitor was prepared and used in NMR experiments to confirm formation of a hemiacetal intermediate on binding with α-chymotrypsin. Analysis of an X-ray crystallographic structure in complex with α-chymotrypsin reveals that the backbone adopts a stable β-strand conformation as per its design. Binding is further stabilised by interaction with the oxyanion hole near the S1 subsite and multiple hydrogen bonds.
authors.affiliation: ARC Centre of Excellence for Nanoscale BioPhotonics (CNBP), Institute for Photonics and Advanced Sensing, Department of Chemistry, The University of Adelaide, Adelaide, SA 5005, Australia. andrew.abell@adelaide.edu.au.
authors.forename: X
authors.initials: X
authors.lastname: Zhang
authors.forename: J B
authors.initials: JB
authors.lastname: Bruning
authors.forename: J H
authors.initials: JH
authors.lastname: George
authors.forename: A D
authors.initials: AD
authors.lastname: Abell
mesh_terms: D000447:Aldehydes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002918:Chymotrypsin / Q000037:antagonists & inhibitors*; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D047028:Macrocyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D015394:Molecular Structure; D057786:Peptidomimetics / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000447:Aldehydes; D004791:Enzyme Inhibitors; D047028:Macrocyclic Compounds; D057786:Peptidomimetics; D002918:Chymotrypsin; C117608:alpha-chymotrypsin