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Researchers Map a Complex Molecular Assembly "Landscape" For the First Time

Information May Offer New Insights into Drug Resistance

LA JOLLA, CA, December 2, 2005—For the first time, scientists at The Scripps Research Institute have developed a highly detailed kinetic and thermodynamic landscape that describes the mechanisms of macromolecular synthesis, findings that may help spur advances in the global challenges of antibiotic drug resistance. In their study, the researchers showed that assembly of the 30S ribosomal subunit is a "complex dance" in which 20 smaller proteins bind to ribosomal RNA (rRNA) as it folds, allowing it to play a major role in the translation of messenger RNA (mRNA), which encodes and carries information from DNA to protein synthesis sites.

"The 30S ribosomal subunit is important because it's the molecular target of a number of commonly used antibiotics," investigator James Williamson said. Williamson, who led the study, is associate dean of the Scripps Research Kellogg School of Science and Technology, professor in the Department of Molecular Biology, and member of The Skaggs Institute for Chemical Biology. "It's critical that we understand how those antibiotics interfere with ribosome assembly and function. To do that, we first have to know the principles that govern the folding and assembly of these large complexes. We used a variety of biochemistry tools, including fluorescence, calorimetry, and mass spectrometry to map the assembly of the 30S subunit—when it folds and when proteins bind to it."

The study's use of these imaging methods allows this intercellular landscape to be "seen" for the first time, making it possible to construct an accurate assembly framework for other large macromolecular complexes that could help scientists create new ways to combat the recent emergence of drug resistant strains of bacteria. This new understanding may also offer insights into a number of other biological mysteries including the origin of life and replication of viruses.

The study is being published by the journal Nature. Co-authors included Megan W. T. Talkington of the Scripps Research Departments of Molecular Biology and Chemistry and The Skaggs Institute for Chemical Biology, and Gary Siuzdak of the Scripps Research Departments of Molecular Biology and Chemistry. The study was supported by a grant from the National Institutes of Health and by predoctoral fellowships from the National Science Foundation and the Skaggs Institute for Chemical Biology.

The study demonstrates the kinetics at which different sites throughout the 30S subunit assemble. Conditions were altered during the study to mimic the intracellular assembly reaction, while various 30S components were engineered to measure the roles of specific components and functional groups including protein folding chaperones. The landscape developed by the study predicts many folding transition points where chaperones might assist.

Williamson's laboratory has been interested in the assembly of the 30S subunit for several years, focusing on the conformation changes that occur in the process. These new findings refute the prevailing view that 30S assembly functions through a single pathway with limited conformational changes to one in which the complex assembly follows a landscape filled with a variety of conformational transitions.

The 30S subunit of the bacterial ribosome is the best model for biophysical analysis of RNA/protein complexes, the large self-assembling machines that drive all fundamental cellular processes. While the ribosome has been associated with protein synthesis since the 1950s and other studies have mapped out the basic series of protein binding events that occur, details of the assembly process were poorly understood until now.

 "The understanding that has emerged from this study of the 30S assembly landscape offers tremendous insights into ribonucleoproteins and other large molecular complexes in general," Williamson said. "It gives us a general assay that is suitable for site-specific assembly in a range of multi-component complexes."

About The Scripps Research Institute

The Scripps Research Institute, headquartered in La Jolla, California, in 15 buildings on 10 acres overlooking the Pacific Ocean, is one of the world's largest independent, non-profit biomedical research organizations. It stands at the forefront of basic biomedical science that seeks to comprehend the most fundamental processes of life. Scripps Research is internationally recognized for its research into immunology, molecular and cellular biology, chemistry, neurosciences, autoimmune, cardiovascular, and infectious diseases, and synthetic vaccine development. Established in its current configuration in 1961, it employs approximately 3,000 scientists, postdoctoral fellows, scientific and other technicians, doctoral degree graduate students, and administrative and technical support personnel.

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