A mechanistic study on the inhibition of α-chymotrypsin by a macrocyclic peptidomimetic aldehyde
X Zhang1, J B Bruning, J H George
1ARC 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.
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.
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