Structural Biology of the Ribosome

Bacterial ribosomes are a major drug target for treating infectious diseases, and more than half of all antibiotics interfere with protein synthesis. The ribosome is a large and complex cellular machine that translates genetic information into proteins, which in turn carry out most of the metabolic functions required for cellular life. Because this translation from nucleic acids into amino acids is a fundamental process, ribosomes are present in all forms of life. Many antibiotic drugs (eg. streptomycin, the first drug to treat tuberculosis) bind selectively to bacterial ribosomes and disrupt protein synthesis, ultimately killing the disease causing bacteria. Mutations within ribosomes that disrupt antibiotic binding sites or enable ribosomes to function in the presence of these antibiotic compounds are one cause for the emergence of resistance against ribosome targeting antibiotics. Structural studies of ribosomes carrying these antibiotic-resistance mutations are a powerful tool for understanding the molecular mechanism of resistance. This, in turn, can provide new leads for the development of new or modified compounds, which are active against resistant pathogens.
Our studies of the ribosome are carried out in a close collaboration with Drs. Albert Dahlberg and Steven Gregory here at Brown University. We use the bacterium Thermus thermophilus as a model system because this organism is amenable to both genetic and structural studies. Ribosomal mutations that result in resistance to streptomycin or a number of other antibiotic compounds have been identified and characterized in the laboratories of Dr. Dahlberg and Dr. Gregory. Because of the powerful combination of genetic expertise in the Dahlberg and Gregory laboratories and of crystallographic expertise in our laboratory, we are in a unique position to systematically examine mutant ribosome structures.
With ongoing experiments, we currently explore two broad areas of research. For the first area, we investigate the mechanism of antibiotic resistance and the impact of mutations and post-transcriptional modifications on ribosome structure and function. For the second area, we study ribosome modifying enzymes and other multi-specific enzymes to understand the molecular basis for multi-specific enzymatic activity.