The advent of higher resolution cryo electron microscopy and structures of eukaryotic ribosomes has opened the field of ribosome mechanism to a vast array of possibilities. Together with the Christian Spahn cryo-EM lab, we recently published one of the first all-atom models of the human ribosome in various functional states related to decoding. Using our MDfit method, we produced models highly consistent with cryo-EM density. The study revealed a new conformational change specific to eukaryotes: subunit rolling. We have also performed extensive studies on tRNA accommodation into the bacterial ribosome. Here, we will investigate the effect of subunit rolling on accommodation during decoding by the mammalian ribosome. We will also study conformational changes occurring prior to decoding and after accommodation. By comparing human and bacterial ribosome mechanism, we hope to gain insight into antibiotic action mechanism. We will use a combination of explicit solvent and all-atom reduced description techniques based on our previous publications. We will also extend our MDfit technique for higher resolution cryo-EM density.

Public Health Relevance

The advent of higher resolution cryo electron microscopy and structures of eukaryotic ribosomes has opened the field of ribosome mechanism to a vast array of possibilities. We will expand on our published studies of tRNA accommodation and human ribosomal decoding, producing simulations of the decoding process in humans. By comparing human and bacteria ribosome mechanism, we hope to gain new insight into antibiotic mechanism.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM072686-12
Application #
8964724
Study Section
Macromolecular Structure and Function D Study Section (MSFD)
Program Officer
Preusch, Peter
Project Start
2005-07-01
Project End
2019-06-30
Budget Start
2015-09-01
Budget End
2016-06-30
Support Year
12
Fiscal Year
2015
Total Cost
$336,489
Indirect Cost
$105,167
Name
Los Alamos National Lab
Department
Type
DUNS #
175252894
City
Los Alamos
State
NM
Country
United States
Zip Code
87545
Liu, Wei; Shin, Dongwon; Ng, Martin et al. (2017) Stringent Nucleotide Recognition by the Ribosome at the Middle Codon Position. Molecules 22:
Budkevich, Tatyana V; Giesebrecht, Jan; Behrmann, Elmar et al. (2014) Regulation of the mammalian elongation cycle by subunit rolling: a eukaryotic-specific ribosome rearrangement. Cell 158:121-31
Kaushal, Prem S; Sharma, Manjuli R; Booth, Timothy M et al. (2014) Cryo-EM structure of the small subunit of the mammalian mitochondrial ribosome. Proc Natl Acad Sci U S A 111:7284-9
Whitford, Paul C; Sanbonmatsu, Karissa Y (2013) Simulating movement of tRNA through the ribosome during hybrid-state formation. J Chem Phys 139:121919
Whitford, Paul C; Blanchard, Scott C; Cate, Jamie H D et al. (2013) Connecting the kinetics and energy landscape of tRNA translocation on the ribosome. PLoS Comput Biol 9:e1003003
Hayes, Ryan L; Noel, Jeffrey K; Mohanty, Udayan et al. (2012) Magnesium fluctuations modulate RNA dynamics in the SAM-I riboswitch. J Am Chem Soc 134:12043-53
Shi, Xinying; Khade, Prashant K; Sanbonmatsu, Karissa Y et al. (2012) Functional role of the sarcin-ricin loop of the 23S rRNA in the elongation cycle of protein synthesis. J Mol Biol 419:125-38
Ahmed, Aqeel; Whitford, Paul C; Sanbonmatsu, Karissa Y et al. (2012) Consensus among flexible fitting approaches improves the interpretation of cryo-EM data. J Struct Biol 177:561-70
Whitford, Paul C; Sanbonmatsu, Karissa Y; Onuchic, José N (2012) Biomolecular dynamics: order-disorder transitions and energy landscapes. Rep Prog Phys 75:076601
Sanbonmatsu, Karissa Y (2012) Computational studies of molecular machines: the ribosome. Curr Opin Struct Biol 22:168-74

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