title: Crystal structure of the bacterial ribosomal decoding site complexed with a synthetic doubly functionalized paromomycin derivative: a new specific binding mode to an a-minor motif enhances in vitro antibacterial activity.
abstract: The crystal structure of the complex between oligonucleotide containing the bacterial ribosomal decoding site (A site) and the synthetic paromomycin analogue 1, which contains the gamma-amino-alpha-hydroxybutyryl (L-haba) group at position N1 of ring II (2-DOS ring), and an ether chain with an O-phenethylaminoethyl group at position C2'' of ring III, is reported. Interestingly, next to the paromomycin analogue 1 specifically bound to the A site, a second molecule of 1 with a different conformation is observed at the crystal packing interface which mimics the A-minor interaction between two bulged-out adenines from the A site and the codon-anticodon stem of the mRNA-tRNA complex. Improved antibacterial activity supports the conclusion that analogue 1 might affect protein synthesis on the ribosome in two different ways: 1) specific binding to the A site forces maintenance of the "on" state with two bulged out adenines, and 2) a new binding mode of 1 to an A-minor motif which stabilizes complex formation between the ribosome and the mRNA-tRNA complex regardless of whether the codon-anticodon stem is of the cognate or near-cognate type.
authors.affiliation: Architecture et Réactivité de l'ARN, Université Louis Pasteur, Institut de Biologie Moléculaire et Cellulaire, CNRS, 15 rue René Descartes, 67084 Strasbourg, France.
authors.forename: Jiro
authors.initials: J
authors.lastname: Kondo
authors.forename: Kandasamy
authors.initials: K
authors.lastname: Pachamuthu
authors.forename: Boris
authors.initials: B
authors.lastname: François
authors.forename: Janek
authors.initials: J
authors.lastname: Szychowski
authors.forename: Stephen
authors.initials: S
authors.lastname: Hanessian
authors.forename: Eric
authors.initials: E
authors.lastname: Westhof
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000378:metabolism; D001419:Bacteria / Q000737:chemistry / Q000187:drug effects* / Q000235:genetics; D001665:Binding Sites; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D009690:Nucleic Acid Conformation; D010303:Paromomycin / Q000737:chemistry* / Q000378:metabolism; D012329:RNA, Bacterial / Q000737:chemistry* / Q000378:metabolism; D012335:RNA, Ribosomal / Q000737:chemistry* / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D012329:RNA, Bacterial; D012335:RNA, Ribosomal; D010303:Paromomycin