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

Nature Chemical Biology volume 7, pages 748–755 (2011)Cite this article

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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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Figure 1: Overall structure and tertiary interactions of the dG-bound M. florum riboswitch.
Figure 2: Structural features of the dG-binding pocket.
Figure 3: Comparison of junctional regions above the ligand-binding pockets in the dG and guanine riboswitches.
Figure 4: Tertiary loop-loop interactions in the dG riboswitch.
Figure 5: Specificity of dG recognition by the riboswitch.
Figure 6: Summary of dG recognition.

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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.

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  1. Alexander Serganov

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

Authors and 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.

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Correspondence to Dinshaw J Patel or Alexander Serganov.

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The authors declare no competing financial interests.

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Pikovskaya, O., Polonskaia, A., Patel, D. et al. Structural principles of nucleoside selectivity in a 2′-deoxyguanosine riboswitch. Nat Chem Biol 7, 748–755 (2011). https://doi.org/10.1038/nchembio.631

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