title: Staphylococcus aureus elongation factor G--structure and analysis of a target for fusidic acid.
abstract: Fusidic acid (FA) is a bacteriostatic antibiotic that locks elongation factor G (EF-G) on the ribosome in a post-translocational state. It is used clinically against Gram-positive bacteria such as pathogenic strains of Staphylococcus aureus, but no structural information has been available for EF-G from these species. We have solved the apo crystal structure of EF-G from S. aureus to 1.9 Å resolution. This structure shows a dramatically different overall conformation from previous structures of EF-G, although the individual domains are highly similar. Between the different structures of free or ribosome-bound EF-G, domains III-V move relative to domains I-II, resulting in a displacement of the tip of domain IV relative to domain G. In S. aureus EF-G, this displacement is about 25 Å relative to structures of Thermus thermophilus EF-G in a direction perpendicular to that in previous observations. Part of the switch I region (residues 46-56) is ordered in a helix, and has a distinct conformation as compared with structures of EF-Tu in the GDP and GTP states. Also, the switch II region shows a new conformation, which, as in other structures of free EF-G, is incompatible with FA binding. We have analysed and discussed all known fusA-based fusidic acid resistance mutations in the light of the new structure of EF-G from S. aureus, and a recent structure of T. thermophilus EF-G in complex with the 70S ribosome with fusidic acid [Gao YG et al. (2009) Science326, 694-699]. The mutations can be classified as affecting FA binding, EF-G-ribosome interactions, EF-G conformation, and EF-G stability.
authors: Department of Cell and Molecular Biology, Uppsala University, Uppsala, Sweden.
authors: Yang
authors: Y
authors: Chen
authors: Ravi Kiran
authors: RK
authors: Koripella
authors: Suparna
authors: S
authors: Sanyal
authors: Maria
authors: M
authors: Selmer
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001059:Apoproteins / Q000737:chemistry / Q000378:metabolism; D018360:Crystallography, X-Ray; D024881:Drug Resistance, Bacterial / Q000235:genetics; D005672:Fusidic Acid / Q000494:pharmacology*; D008968:Molecular Conformation; D009154:Mutation; D020653:Peptide Elongation Factor G / Q000737:chemistry* / Q000378:metabolism*; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D016601:RNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000378:metabolism; D012270:Ribosomes / Q000737:chemistry / Q000378:metabolism; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000378:metabolism*
chemical_list: D000900:Anti-Bacterial Agents; D001059:Apoproteins; C492444:FusA protein, Staphylococcus aureus; D020653:Peptide Elongation Factor G; D016601:RNA-Binding Proteins; D011993:Recombinant Fusion Proteins; D005672:Fusidic Acid