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Updated: Aug 16, 2026

Antimicrobial Peptides Produced by Selective Pressure Incorporation of Non-canonical Amino Acids
Published on: May 4, 2018
Unique binding of a non-natural L,L,L-substrate by isopenicillin N synthase
Annaleise R Howard-Jones1, Peter J Rutledge, Ian J Clifton
1Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK. annaleise_howard-jones@hms.harvard.edu
Abstract:
Isopenicillin N synthase (IPNS) is a non-haem iron oxidase that catalyses the formation of isopenicillin N from the tripeptide delta-(L-alpha-aminoadipoyl)-L-cysteinyl-D-valine. In this report, we describe the crystal structure of the enzyme with a non-natural L,L,L-tripeptide substrate, delta-(L-alpha-aminoadipoyl)-L-cysteinyl-L-3,3,3,3',3',3'-hexafluorovaline. This structure reveals a strong binding interaction of the tripeptide within the active site and a unique conformation for the non-natural L,L,L-diastereomer. Taken together, these findings provide a possible rationale for the previously observed inhibitory effects of L,L,L-tripeptide substrates on IPNS activity.
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