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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Program Projects (P01)
Project #
5P01GM022778-38
Application #
8450793
Study Section
Special Emphasis Panel (ZRG1-BCMB-K (40))
Program Officer
Flicker, Paula F
Project Start
1997-04-01
Project End
2014-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
38
Fiscal Year
2013
Total Cost
$1,425,876
Indirect Cost
$562,270
Name
Yale University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
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Wang, Jimin; Wing, Richard A (2014) Diamonds in the rough: a strong case for the inclusion of weak-intensity X-ray diffraction data. Acta Crystallogr D Biol Crystallogr 70:1491-7
Roth, Adam; Weinberg, Zasha; Chen, Andy G Y et al. (2014) A widespread self-cleaving ribozyme class is revealed by bioinformatics. Nat Chem Biol 10:56-60
Wang, Jimin; Li, Yue; Modis, Yorgo (2014) Exploiting subtle structural differences in heavy-atom derivatives for experimental phasing. Acta Crystallogr D Biol Crystallogr 70:1873-83
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Polikanov, Yury S; Steitz, Thomas A; Innis, C Axel (2014) A proton wire to couple aminoacyl-tRNA accommodation and peptide-bond formation on the ribosome. Nat Struct Mol Biol 21:787-93
Askerka, Mikhail; Wang, Jimin; Brudvig, Gary W et al. (2014) Structural changes in the oxygen-evolving complex of photosystem II induced by the S1 to S2 transition: A combined XRD and QM/MM study. Biochemistry 53:6860-2
Polikanov, Yury S; Szal, Teresa; Jiang, Fuyan et al. (2014) Negamycin interferes with decoding and translocation by simultaneous interaction with rRNA and tRNA. Mol Cell 56:541-50
Wang, Jimin; Li, Yue; Modis, Yorgo (2014) Structural models of the membrane anchors of envelope glycoproteins E1 and E2 from pestiviruses. Virology 454-455:93-101
Nelson, James W; Sudarsan, Narasimhan; Furukawa, Kazuhiro et al. (2013) Riboswitches in eubacteria sense the second messenger c-di-AMP. Nat Chem Biol 9:834-9

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