Ribosome antibiotic complexes antibiotics bound

Rational efforts to design new antibiotics that target the ribosome became feasible when the crystal structures of both ribosomal subunits were solved at atomic resolution in 2000 [1-3]. Since then, structures of about 20 different antibiotics bound to ribosomes have been published (Tab. 4.1) [4—12]. These structures of antibiotic/ribosomal complexes provide insights into the mechanisms by which antibiotics inhibit protein synthesis and by which mutations confer resistance. Thus, a sound basis now exists for designing new antibiotics that may circumvent resistance. 

Fig. 4.5 Overview of antibiotics bound at the peptidyl transferase center. A surface representation of the large subunit of H. marismortui includes the P-site, A-site and entrance to the peptide exit tunnel. Most of these antibiotics contact either the active site hydro-phobic crevice (green surface, upper center) or the hydrophobic crevice at the entrance to the exit tunnel (green surface, lower right). In addition, many of these antibiotics occupy an elongated pocket (dark surface, center) in the wall of the exit tunnel between these two crevices. The antibiotics shown are all from complexes with H. marismortui ribosomes and overlap the binding site of A-site substrates (red sticks) or of a P-site substrates (orange sticks). Fig. modified from...

The possibility of errors in deposited structures must be considered. Errors in chirality may be prevalent in high resolution small molecule structures. For example, the small molecule structure of streptogramin A is represented by its enantiomer in the Cambridge Structural Data Base. The effort to solve the structure of streptogramin A bound to the ribosome was initially hindered by relying on that incorrect small molecule structure. Likewise, the structure of anisomycin is incorrectly diagrammed as its enantiomer in most of the ribosomal literature. Fortunately, these chirality errors were identified when solving structures of these antibiotics bound to macromolecules. In fact, the identification of these errors may increase confidence in the reliability of these structures of complexes between ribosomes and antibiotics. 

---