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Structural principles of nucleoside selectivity in a 2′-deoxyguanosine riboswitch

Nature Chemical Biology volume 7, pages 748755 (2011) | Download Citation

Abstract

Purine riboswitches have an essential role in genetic regulation of bacterial metabolism. This family includes the 2′-deoxyguanosine (dG) riboswitch, which is involved in feedback control of deoxyguanosine biosynthesis. To understand the principles that define dG selectivity, we determined crystal structures of the natural Mesoplasma florum riboswitch bound to cognate dG as well as to noncognate guanosine, deoxyguanosine monophosphate and guanosine monophosphate. Comparison with related purine riboswitch structures reveals that the dG riboswitch achieves its specificity through modification of key interactions involving the nucleobase and rearrangement of the ligand-binding pocket to accommodate the additional sugar moiety. In addition, we observe new conformational changes beyond the junctional binding pocket extending as far as peripheral loop-loop interactions. It appears that re-engineering riboswitch scaffolds will require consideration of selectivity features dispersed throughout the riboswitch tertiary fold, and structure-guided drug design efforts targeted to junctional RNA scaffolds need to be addressed within such an expanded framework.

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Acknowledgements

We thank the personnel of beamline X29 at the Brookhaven National Laboratory, funded by the US Department of Energy, for assistance in data collection. We thank O. Ouerfelli (Memorial Sloan-Kettering Cancer Center, New York) for the synthesis of iridium hexamine and E. Ennifar (Institut de Biologie Moléculaire et Cellulaire, Strasbourg) for the discussion of the refinement strategy. D.J.P. was supported by funds from the US National Institutes of Health grant GM66354.

Author information

Author notes

    • Alexander Serganov

    Current address: Department of Biochemistry, New York University School of Medicine, New York, New York, USA.

Affiliations

  1. Structural Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.

    • Olga Pikovskaya
    • , Anna Polonskaia
    • , Dinshaw J Patel
    •  & Alexander Serganov

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Contributions

A.P. and O.P. crystallized the riboswitch. O.P. determined the structures. O.P. and A.S. refined the structures and performed binding experiments. A.S. and D.J.P. wrote the manuscript. All authors discussed the results and commented on the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Dinshaw J Patel or Alexander Serganov.

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    Supplementary Figures 1–9, Supplementary Tables 1–2 and Supplementary Results

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DOI

https://doi.org/10.1038/nchembio.631

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