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, and ribo-switches will be studied. While a major technique to be 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 the structures of 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 mechanisms of riboswitches and other RNAs using allosteric mechanisms, the mechanisms of catalysis by various ribozymes. 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 that are 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 and riboswitches, are important targets of antibiotics. Understanding the relationships between their structures and functions is essential to understanding their mechanisms of action and developing new classes of molecules.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Program Projects (P01)
Project #
5P01GM022778-41
Application #
9254567
Study Section
Special Emphasis Panel (ZRG1-BCMB-R (40)P)
Program Officer
Flicker, Paula F
Project Start
1997-04-01
Project End
2020-03-31
Budget Start
2017-04-01
Budget End
2018-03-31
Support Year
41
Fiscal Year
2017
Total Cost
$1,158,862
Indirect Cost
$451,976
Name
Yale University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Greenlee, Etienne B; Stav, Shira; Atilho, Ruben M et al. (2018) Challenges of ligand identification for the second wave of orphan riboswitch candidates. RNA Biol 15:377-390
Mirihana Arachchilage, Gayan; Sherlock, Madeline E; Weinberg, Zasha et al. (2018) SAM-VI RNAs selectively bind S-adenosylmethionine and exhibit similarities to SAM-III riboswitches. RNA Biol 15:371-378
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; 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 :
Harris, Kimberly A; Zhou, Zhiyuan; Peters, Michelle L et al. (2018) A second RNA-binding protein is essential for ethanol tolerance provided by the bacterial OLE ribonucleoprotein complex. Proc Natl Acad Sci U S A 115:E6319-E6328
Li, Sanshu; Breaker, Ronald R (2017) Identification of 15 candidate structured noncoding RNA motifs in fungi by comparative genomics. BMC Genomics 18:785

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