title: Structure of MurF from Streptococcus pneumoniae co-crystallized with a small molecule inhibitor exhibits interdomain closure.
abstract: In a broad genomics analysis to find novel protein targets for antibiotic discovery, MurF was identified as an essential gene product for Streptococcus pneumonia that catalyzes a critical reaction in the biosynthesis of the peptidoglycan in the formation of the cell wall. Lacking close relatives in mammalian biology, MurF presents attractive characteristics as a potential drug target. Initial screening of the Abbott small-molecule compound collection identified several compounds for further validation as pharmaceutical leads. Here we report the integrated efforts of NMR and X-ray crystallography, which reveal the multidomain structure of a MurF-inhibitor complex in a compact conformation that differs dramatically from related structures. The lead molecule is bound in the substrate-binding region and induces domain closure, suggestive of the domain arrangement for the as yet unobserved transition state conformation for MurF enzymes. The results form a basis for directed optimization of the compound lead by structure-based design to explore the suitability of MurF as a pharmaceutical target.
authors.affiliation: Department of Structural Biology, R46Y, Building AP10, 100 Abbott Park Road, Abbott Park, IL 60064, USA. Kenton.Longenecker@Abbott.com
authors.forename: Kenton L
authors.initials: KL
authors.lastname: Longenecker
authors.forename: Geoffrey F
authors.initials: GF
authors.lastname: Stamper
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Hajduk
authors.forename: Elizabeth H
authors.initials: EH
authors.lastname: Fry
authors.forename: Clarissa G
authors.initials: CG
authors.lastname: Jakob
authors.forename: John E
authors.initials: JE
authors.lastname: Harlan
authors.forename: Rohinton
authors.initials: R
authors.lastname: Edalji
authors.forename: Diane M
authors.initials: DM
authors.lastname: Bartley
authors.forename: Karl A
authors.initials: KA
authors.lastname: Walter
authors.forename: Larry R
authors.initials: LR
authors.lastname: Solomon
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Holzman
authors.forename: Yu Gui
authors.initials: YG
authors.lastname: Gu
authors.forename: Claude G
authors.initials: CG
authors.lastname: Lerner
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Beutel
authors.forename: Vincent S
authors.initials: VS
authors.lastname: Stoll
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D019906:Nuclear Magnetic Resonance, Biomolecular; D010453:Peptide Synthases / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment; D017385:Sequence Homology; D013296:Streptococcus pneumoniae / Q000201:enzymology*; D013379:Substrate Specificity
chemical_list: D004791:Enzyme Inhibitors; D008024:Ligands; D010453:Peptide Synthases; C060628:UDP-N-acetylmuramoylalanyl-D-glutamyllysine-D-alanyl-D-alanine ligase