title: Structural and functional characterization of enantiomeric glutamic acid derivatives as potential transition state analogue inhibitors of MurD ligase.
abstract: Mur ligases play an essential role in the intracellular biosynthesis of bacterial peptidoglycan, the main component of the bacterial cell wall, and represent attractive targets for the design of novel antibacterials. UDP-N-acetylmuramoyl-L-alanine:D-glutamate ligase (MurD) catalyses the addition of D-glutamic acid to the cytoplasmic intermediate UDP-N-acetylmuramoyl-L-alanine (UMA) and is the second in the series of Mur ligases. MurD ligase is highly stereospecific for its substrate, D-glutamic acid (D-Glu). Here, we report the high resolution crystal structures of MurD in complexes with two novel inhibitors designed to mimic the transition state of the reaction, which contain either the D-Glu or the L-Glu moiety. The binding modes of N-sulfonyl-D-Glu and N-sulfonyl-L-Glu derivatives were also characterised kinetically. The results of this study represent an excellent starting point for further development of novel inhibitors of this enzyme.
authors.affiliation: Lek Pharmaceuticals d. d., Drug Discovery, Verovskova 57, 1526 Ljubljana, Slovenia. miha.kotnik@sandoz.com <miha.kotnik@sandoz.com>
authors.forename: Miha
authors.initials: M
authors.lastname: Kotnik
authors.forename: Jan
authors.initials: J
authors.lastname: Humljan
authors.forename: Carlos
authors.initials: C
authors.lastname: Contreras-Martel
authors.forename: Marko
authors.initials: M
authors.lastname: Oblak
authors.forename: Katja
authors.initials: K
authors.lastname: Kristan
authors.forename: Mireille
authors.initials: M
authors.lastname: Hervé
authors.forename: Didier
authors.initials: D
authors.lastname: Blanot
authors.forename: Uros
authors.initials: U
authors.lastname: Urleb
authors.forename: Stanislav
authors.initials: S
authors.lastname: Gobec
authors.forename: Andréa
authors.initials: A
authors.lastname: Dessen
authors.forename: Tom
authors.initials: T
authors.lastname: Solmajer
mesh_terms: D001665:Binding Sites; D018360:Crystallography, X-Ray; D004926:Escherichia coli / Q000201:enzymology; D029968:Escherichia coli Proteins / Q000737:chemistry / Q000378:metabolism; D018698:Glutamic Acid / Q000031:analogs & derivatives*; D008024:Ligands; D008025:Ligases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D015394:Molecular Structure; D011485:Protein Binding; D011487:Protein Conformation; D013379:Substrate Specificity
chemical_list: D029968:Escherichia coli Proteins; D008024:Ligands; D018698:Glutamic Acid; D008025:Ligases