Inhibition of α-chymotrypsin

Michelle-Zhang_1_sq23 June 2016:

CNBP researchers Xiaozhou (Michelle) Zhang  (pictured left) and Prof Andrew Abell (CNBP Chief Investigator) report on an NMR and X-ray crystallography-based characterisation of the mechanism by which a new class of macrocyclic peptidomimetic aldehyde inhibits α-chymotrypsin.

This provides molecular level insight into the mechanism and functionalities of proteases, which are crucial for many biological systems including neuronal, embryonic and cardiovascular systems.

Journal: Organic & Biomolecular Chemistry

Publication title: A mechanistic study on the inhibition of α-chymotrypsin by a macrocyclic peptidomimetic aldehyde.

Authors: X. Zhang, J. B. Bruning, J. H. George and A. D. Abell

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 13C-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.

The paper is accessible online.