title: Structural basis for the interaction of antibiotics with the peptidyl transferase centre in eubacteria.
abstract: Ribosomes, the site of protein synthesis, are a major target for natural and synthetic antibiotics. Detailed knowledge of antibiotic binding sites is central to understanding the mechanisms of drug action. Conversely, drugs are excellent tools for studying the ribosome function. To elucidate the structural basis of ribosome-antibiotic interactions, we determined the high-resolution X-ray structures of the 50S ribosomal subunit of the eubacterium Deinococcus radiodurans, complexed with the clinically relevant antibiotics chloramphenicol, clindamycin and the three macrolides erythromycin, clarithromycin and roxithromycin. We found that antibiotic binding sites are composed exclusively of segments of 23S ribosomal RNA at the peptidyl transferase cavity and do not involve any interaction of the drugs with ribosomal proteins. Here we report the details of antibiotic interactions with the components of their binding sites. Our results also show the importance of putative Mg+2 ions for the binding of some drugs. This structural analysis should facilitate rational drug design.
authors.affiliation: Max-Planck-Research, Unit for Ribosomal Structure, Notkestrasse 85, 22603 Hamburg, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Schlünzen
authors.forename: R
authors.initials: R
authors.lastname: Zarivach
authors.forename: J
authors.initials: J
authors.lastname: Harms
authors.forename: A
authors.initials: A
authors.lastname: Bashan
authors.forename: A
authors.initials: A
authors.lastname: Tocilj
authors.forename: R
authors.initials: R
authors.lastname: Albrecht
authors.forename: A
authors.initials: A
authors.lastname: Yonath
authors.forename: F
authors.initials: F
authors.lastname: Franceschi
mesh_terms: D000900:Anti-Bacterial Agents / Q000378:metabolism*; D001419:Bacteria / Q000378:metabolism*; D001483:Base Sequence; D001665:Binding Sites; D002701:Chloramphenicol / Q000378:metabolism; D018360:Crystallography, X-Ray; D018942:Macrolides / Q000378:metabolism; D008274:Magnesium / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010458:Peptidyl Transferases / Q000378:metabolism*; D011487:Protein Conformation; D012329:RNA, Bacterial / Q000378:metabolism; D012338:RNA, Ribosomal, 23S / Q000378:metabolism; D012269:Ribosomal Proteins / Q000378:metabolism; D012270:Ribosomes / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D018942:Macrolides; D012329:RNA, Bacterial; D012338:RNA, Ribosomal, 23S; D012269:Ribosomal Proteins; D002701:Chloramphenicol; D010458:Peptidyl Transferases; D008274:Magnesium