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.
MeSH terms
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Aldehydes / chemical synthesis
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Aldehydes / chemistry
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Aldehydes / pharmacology*
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Chymotrypsin / antagonists & inhibitors*
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Crystallography, X-Ray
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Enzyme Inhibitors / chemical synthesis
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacology*
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Macrocyclic Compounds / chemical synthesis
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Macrocyclic Compounds / chemistry
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Macrocyclic Compounds / pharmacology*
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Magnetic Resonance Spectroscopy
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Models, Molecular
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Molecular Structure
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Peptidomimetics / chemical synthesis
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Peptidomimetics / chemistry
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Peptidomimetics / pharmacology*
Substances
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Aldehydes
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Enzyme Inhibitors
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Macrocyclic Compounds
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Peptidomimetics
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Chymotrypsin
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alpha-chymotrypsin