Targeting Functional Centers of the Ribosome [Paperback]

This thesis describes research into the mode of function, inhibition, and evolution of the ribosomal catalytic center, the Peptidyl Transferase Center (PTC)--research that has already led to attempts at improving PTC antibiotics. The PhD candidate carried out two parallel studies. One using a combination of X-ray crystallography, biochemistry, molecular biology, and theoretical studies to obtain crystal structures of ribosomal particles with antibiotics that target the PTC, revealing the modes of action, resistance, cross-resistance and discrimination between ribosomes of eubacterial pathogens and eukaryotic hosts. In the second parallel study, the candidate synthesized a ribosomal substructure--one that may represent the minimal entity capable of catalyzing peptide bond formation--shedding light on the origin of the ribosome itself.

1. Introduction?

1.1 Ribosomal antibiotics: function, activity and selectivity??????????

1.2 Pleuromutilins: a class of PTC ribosomal antibiotics for clinical use??

1.3 Structural basis for cross-resistance between ribosomal PTC antibiotics?????????

1.4 Oligonucleotides as ribosomal inhibitors and as tools for structural and functional study??????

1.5 Minimal ribosomal components with PTC structure and function??????

2. Methods????????

2.1 Structural study of pleuromutilin antibiotics??????????????

2.1.1 Crystallization and data collection

2.1.2 Data processing, structure solution and refinement??????????????

2.2 Comparative structural analysis to reveal the structural basis for crolC=