BSA Distinguished Lecture

The ribosome is a very large macromolecular machine that translates genes encoded in mRNA into proteins in all living cells. It is made out of two-thirds RNA and one third protein, and our structural studies of the larger of the two subunits bound to substrate analogues have shown that the RNA component is responsible for catalyzing the reaction that ties the amino acids together: as Francis Crick suggested in 1968 – the ribosome is a ribozyme.

During the process of protein synthesis elongation, the 70S ribosome is in various conformational states bound to various different protein factors that play critical roles in the steps of protein synthesis. We have now determined the structures of these functional states are beginning to emerge.

The ribosome is a major target of antibiotics, and we also determined the structures of many complexes of the ribosome with different families of antibiotics. The structures of some of our antibiotic complexes have been used by Rib-X Pharmaceuticals, Inc. of New Haven to develop new potential antibiotic compounds that are effective against MRSA, one of which has successfully completed phase II clinical trials. Recently, we have determined the crystal structures of the 70S ribosome bound to two compounds that are effective against tuberculosis, capreomycin and viomycin. Since their binding site is adjacent to those of two antibiotics that bind to the small subunit, the design of new anti-TB antibiotics by chemically combining components of the neighboring compounds should be possible.