title: Mirror-Image Packing Provides a Molecular Basis for the Nanomolar Equipotency of Enantiomers of an Experimental Herbicide.
abstract: Programs of drug discovery generally exploit one enantiomer of a chiral compound for lead development following the principle that enantiomer recognition is central to biological specificity. However, chiral promiscuity has been identified for a number of enzyme families, which have shown that mirror-image packing can enable opposite enantiomers to be accommodated in an enzyme's active site. Reported here is a series of crystallographic studies of complexes between an enzyme and a potent experimental herbicide whose chiral center forms an essential part of the inhibitor pharmacophore. Initial studies with a racemate at 1.85 Å resolution failed to identify the chirality of the bound inhibitor, however, by extending the resolution to 1.1 Å and by analyzing high-resolution complexes with the enantiopure compounds, we determined that both enantiomers make equivalent pseudosymmetric interactions in the active site, thus mimicking an achiral reaction intermediate.
authors.affiliation: Krebs Institute for Biomolecular Research, Department of Molecular Biology and Biotechnology, University of Sheffield, Firth Court, Western Bank, Sheffield, S10 2TN, UK.
authors.forename: Claudine
authors.identifier: 0000-0002-9430-6822
authors.initials: C
authors.lastname: Bisson
authors.affiliation: Krebs Institute for Biomolecular Research, Department of Molecular Biology and Biotechnology, University of Sheffield, Firth Court, Western Bank, Sheffield, S10 2TN, UK.
authors.forename: K Linda
authors.initials: KL
authors.lastname: Britton
authors.affiliation: Krebs Institute for Biomolecular Research, Department of Molecular Biology and Biotechnology, University of Sheffield, Firth Court, Western Bank, Sheffield, S10 2TN, UK.
authors.forename: Svetlana E
authors.initials: SE
authors.lastname: Sedelnikova
authors.affiliation: Krebs Institute for Biomolecular Research, Department of Molecular Biology and Biotechnology, University of Sheffield, Firth Court, Western Bank, Sheffield, S10 2TN, UK.
authors.forename: H Fiona
authors.initials: HF
authors.lastname: Rodgers
authors.affiliation: Division of Biological Chemistry and Drug Discovery, Wellcome Trust Biocentre, University of Dundee, Dundee, DD1 5EH, UK.
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Eadsforth
authors.affiliation: Syngenta, Jealott's Hill International Research Station, Bracknell, RG42 6EY, UK.
authors.forename: Russell C
authors.initials: RC
authors.lastname: Viner
authors.affiliation: Syngenta, Jealott's Hill International Research Station, Bracknell, RG42 6EY, UK.
authors.forename: Tim R
authors.initials: TR
authors.lastname: Hawkes
authors.affiliation: Krebs Institute for Biomolecular Research, Department of Molecular Biology and Biotechnology, University of Sheffield, Firth Court, Western Bank, Sheffield, S10 2TN, UK. p.baker@sheffield.ac.uk.
authors.forename: Patrick J
authors.identifier: 0000-0003-1995-5643
authors.initials: PJ
authors.lastname: Baker
authors.affiliation: Krebs Institute for Biomolecular Research, Department of Molecular Biology and Biotechnology, University of Sheffield, Firth Court, Western Bank, Sheffield, S10 2TN, UK. d.rice@sheffield.ac.uk.
authors.forename: David W
authors.initials: DW
authors.lastname: Rice
keywords: chirality; drug design; enantioselectivity; inhibitors; structural biology