title: Structural variation and inhibitor binding in polypeptide deformylase from four different bacterial species.
abstract: Polypeptide deformylase (PDF) catalyzes the deformylation of polypeptide chains in bacteria. It is essential for bacterial cell viability and is a potential antibacterial drug target. Here, we report the crystal structures of polypeptide deformylase from four different species of bacteria: Streptococcus pneumoniae, Staphylococcus aureus, Haemophilus influenzae, and Escherichia coli. Comparison of these four structures reveals significant overall differences between the two Gram-negative species (E. coli and H. influenzae) and the two Gram-positive species (S. pneumoniae and S. aureus). Despite these differences and low overall sequence identity, the S1' pocket of PDF is well conserved among the four enzymes studied. We also describe the binding of nonpeptidic inhibitor molecules SB-485345, SB-543668, and SB-505684 to both S. pneumoniae and E. coli PDF. Comparison of these structures shows similar binding interactions with both Gram-negative and Gram-positive species. Understanding the similarities and subtle differences in active site structure between species will help to design broad-spectrum polypeptide deformylase inhibitor molecules.
authors.affiliation: GlaxoSmithKline, Harlow, Essex CM19 5AW, UK. Kathrine_J_Smith@gsk.com
authors.forename: Kathrine J
authors.initials: KJ
authors.lastname: Smith
authors.forename: Chantal M
authors.initials: CM
authors.lastname: Petit
authors.forename: Kelly
authors.initials: K
authors.lastname: Aubart
authors.forename: Martin
authors.initials: M
authors.lastname: Smyth
authors.forename: Edward
authors.initials: E
authors.lastname: McManus
authors.forename: Jo
authors.initials: J
authors.lastname: Jones
authors.forename: Andrew
authors.initials: A
authors.lastname: Fosberry
authors.forename: Ceri
authors.initials: C
authors.lastname: Lewis
authors.forename: Michael
authors.initials: M
authors.lastname: Lonetto
authors.forename: Siegfried B
authors.initials: SB
authors.lastname: Christensen
mesh_terms: D000581:Amidohydrolases; D000595:Amino Acid Sequence; D000626:Aminopeptidases / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism*; D001665:Binding Sites; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D004926:Escherichia coli / Q000187:drug effects / Q000201:enzymology; D006193:Haemophilus influenzae / Q000187:drug effects / Q000201:enzymology; D007700:Kinetics; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010455:Peptides; D011485:Protein Binding; D011487:Protein Conformation; D017386:Sequence Homology, Amino Acid; D013211:Staphylococcus aureus / Q000187:drug effects / Q000201:enzymology; D013296:Streptococcus pneumoniae / Q000187:drug effects / Q000201:enzymology
chemical_list: D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D010455:Peptides; D000626:Aminopeptidases; D000581:Amidohydrolases; C084507:peptide deformylase