MITOCHONDR RIBOSOME · Structural characterization of a mammalian mitochondrial ribosome and its complexes by the X-ray crystallography

The ribosome is a large ribonucleoprotein particle which translates mRNA to proteins through a sophisticated process that combines high speed and accuracy. It thus plays a central role in protein biosynthesis, translation, which is a fundamental and essential process in all cells. Mitochondria contain a translational system that is distinct from that of the cell cytoplasm. Mitochondrial ribosomes have remarkable divergence from those of bacteria and the eukaryotic cytoplasm. Most of the mitochondrial ribosomal proteins are unique, having no closely related homologues in bacterial or eukaryotic-cytoplasmic ribosomes. Furthermore, mitoribosomes have acquired an intrinsic GTP binding protein. In the proposed project we aim to address several central questions pertaining to the mechanism of mitochondrial ribosome by exploring its three dimensional structure. We take the challenge for the first time to crystallize and determine the X-ray structure of the mitochondrial ribosome from bovine heart mitochondria. A high-resolution structure of the mitoribosome is likely to be a challenging goal. However, we believe the collaboration proposed here that combines the strengths of two groups, V. Ramakrishnan and J. Walker, supplemented by the previous experience of the applicant in determining the structure of large macromolecular complexes containing high non-protein content, provides a unique opportunity to mount an attack on this problem. Studying the mitochondrial ribosome will have an important medical impact due to the fact that many of the adverse side effects of therapeutically important antibacterial antibiotics are ascribed to inhibitory effects on mitochondrial ribosomes, as well as many genetic diseases. The structure determination of mitoribosome is expected to require new approaches in structural biology. Therefore, in addressing questions of large complexes protein structural biology, our efforts will yield high impact beyond understanding translation mechanisms.