The objective of this Program is to develop a fundamental physical and chemical understanding of the mechanisms by which RNA molecules and their complexes with proteins carry out their biological functions. During the next five years, several different systems that are involved in the processes of protein synthesis by ribosomes, catalysis by RNA enzymes, RNA helicases and ribo-switches will be studied. While the primary technique used will be single crystal X-ray diffraction, these structural studies will be integrated with genetic, biochemical, chemical and computational approaches. A major goal will be to capture these macromolecular machines at each step of the various processes they carry out, enabling the production of movies showing the molecular motions involved in these mechanisms. Of special interest are the motions that occur in the course of protein synthesis as the ribosome proceeds through its elongation cycle, the co-translational passage of secreted proteins through membranes, the remodeling of RNA by a DEAD box helicase, the mechanisms of riboswitches and other RNAs using allosteric mechanisms, the allosteric consequence of aminoacyl-tRNA synthetase recognition of the tRNA anticodon, and the mechanism of catalysis by a group I intron RNA. Also of interest will be the ways in which the structures and properties of RNA molecules can be utilized to carry out various biological functions often analogous to those performed by proteins.

Public Health Relevance

RNA is continuing to emerge as a central and vital player in biological function and some, such as the ribosome, are targets of antibiotics. Understanding the relations between their structures and functions is essential.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Program Projects (P01)
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Special Emphasis Panel (ZRG1-BCMB-K (40))
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Flicker, Paula F
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Yale University
Schools of Medicine
New Haven
United States
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Wang, Jimin; Liu, Zheng; Crabtree, Robert H et al. (2018) On the damage done to the structure of the Thermoplasma acidophilum proteasome by electron radiation. Protein Sci 27:2051-2061
Sherlock, Madeline E; Sadeeshkumar, Harini; Breaker, Ronald R (2018) Variant Bacterial Riboswitches Associated with Nucleotide Hydrolase Genes Sense Nucleoside Diphosphates. Biochemistry :
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Wang, Jimin (2018) Determination of chemical identity and occupancy from experimental density maps. Protein Sci 27:411-420
Sherlock, Madeline E; Sudarsan, Narasimhan; Breaker, Ronald R (2018) Riboswitches for the alarmone ppGpp expand the collection of RNA-based signaling systems. Proc Natl Acad Sci U S A 115:6052-6057
Harris, Kimberly A; Breaker, Ronald R (2018) Large Noncoding RNAs in Bacteria. Microbiol Spectr 6:
Yang, Yang; Kang, Dongwei; Nguyen, Laura A et al. (2018) Structural basis for potent and broad inhibition of HIV-1 RT by thiophene[3,2-d]pyrimidine non-nucleoside inhibitors. Elife 7:
Wang, Jimin (2017) On the appearance of carboxylates in electrostatic potential maps. Protein Sci 26:396-402

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