Ribosomes are molecular machines that carry out an essential biological task: they synthesize proteins. Thus, bacterial ribosomes are logical targets for antibiotics. However, the emergence (and growth of) drug resistant bacteria poses a major threat to human health. New strategies for attacking resistant strains must be developed. Recent, breakthrough structural studies of the ribosome enable an entirely new approach to interfering with the ribosome: preventing its self assembly. Here, we propose to develop and apply a new experimental method for measuring structural changes accompanying the real time self-assembly of the ribosome or its subunits. If successful, this approach will enable identification of folding pathways or partially folded states that may be amenable to attack.

Public Health Relevance

Large molecular machines, like the ribosome, are constructed from both RNA and protein precursors. The methods we propose will provide unique insight into self-assembly of large ribonucleoprotein complexes, like the ribosome. A long term goal of this work is to guide development of a new generation of antibiotics that interfere with self-assembly. If the approach is successful, this knowledge brings an additional weapon to the fight against antibiotic resistant bacteria, an escalating threat to human health.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM088645-04
Application #
8310270
Study Section
Special Emphasis Panel (ZGM1-CBB-7 (EU))
Program Officer
Preusch, Peter C
Project Start
2009-08-10
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2014-07-31
Support Year
4
Fiscal Year
2012
Total Cost
$262,965
Indirect Cost
$91,447
Name
Cornell University
Department
Engineering (All Types)
Type
Schools of Engineering
DUNS #
872612445
City
Ithaca
State
NY
Country
United States
Zip Code
14850
Chen, Yujie; Tokuda, Joshua M; Topping, Traci et al. (2014) Revealing transient structures of nucleosomes as DNA unwinds. Nucleic Acids Res 42:8767-76
Grigg, Jason C; Chen, Yujie; Grundy, Frank J et al. (2013) T box RNA decodes both the information content and geometry of tRNA to affect gene expression. Proc Natl Acad Sci U S A 110:7240-5
Blose, Joshua M; Pabit, Suzette A; Meisburger, Steve P et al. (2011) Effects of a protecting osmolyte on the ion atmosphere surrounding DNA duplexes. Biochemistry 50:8540-7
Pabit, Suzette A; Meisburger, Steve P; Li, Li et al. (2010) Counting ions around DNA with anomalous small-angle X-ray scattering. J Am Chem Soc 132:16334-6