The structures of antibiotics bound to the E site region of the 50 S ribosomal subunit of Haloarcula marismortui: 13-deoxytedanolide and girodazole.
Crystal structures of the 50 S ribosomal subunit from Haloarcula marismortui complexed with two antibiotics have identified new sites at which antibiotics interact with the ribosome and inhibit protein synthesis. 13-Deoxytedanolide binds to the E site of the 50 S subunit at the same location as the CCA of tRNA, and thus appears to inhibit protein synthesis by competing with deacylated tRNAs for E site binding. Girodazole binds near the E site region, but is somewhat buried and may inhibit tRNA binding by interfering with conformational changes that occur at the E site. The specificity of 13-deoxytedanolide for eukaryotic ribosomes is explained by its extensive interactions with protein L44e, which is an E site component of archaeal and eukaryotic ribosomes, but not of eubacterial ribosomes. In addition, protein L28, which is unique to the eubacterial E site, overlaps the site occupied by 13-deoxytedanolide, precluding its binding to eubacterial ribosomes. Girodazole is specific for eukarytes and archaea because it makes interactions with L15 that are not possible in eubacteria.
Schroeder
Susan J
SJ
Department of Chemistry, Yale University, New Haven, CT 06520-8107, USA.
Blaha
Gregor
G
Tirado-Rives
Julian
J
Steitz
Thomas A
TA
Moore
Peter B
PB
D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000378:metabolism; D001667:Binding, Competitive; D019614:Haloarcula marismortui; D057927:Hydrophobic and Hydrophilic Interactions; D007093:Imidazoles / Q000737:chemistry* / Q000378:metabolism*; D018942:Macrolides / Q000737:chemistry* / Q000378:metabolism*; D008958:Models, Molecular; D011412:Propanolamines / Q000737:chemistry* / Q000378:metabolism*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D021122:Protein Subunits / Q000737:chemistry / Q000378:metabolism; D012269:Ribosomal Proteins / Q000737:chemistry / Q000378:metabolism*
C409106:13-deoxytedanolide; D000900:Anti-Bacterial Agents; D007093:Imidazoles; D018942:Macrolides; D011412:Propanolamines; D021122:Protein Subunits; D012269:Ribosomal Proteins; C072834:girodazole