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

Purine riboswitches play an essential role in genetic regulation of bacterial metabolism. This family includes the 2′-deoxyguanosine (dG) riboswitch, involved in feedback control of deoxyguanosine biosynthesis. To understand the principles that define dG selectivity, we determined crystal structures of natural Mesoplasma florum riboswitch bound to cognate dG, as well as non-cognate guanosine, deoxyguanosine monophosphate and guanosine monophosphate. Comparison with related purine riboswitch structures reveals that the dG riboswitch achieves its specificity by modifying key interactions involving the nucleobase and through rearrangement of the ligand-binding pocket, so as to accommodate the additional sugar moiety. In addition, we observe novel 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 that structure-guided drug design efforts targeted to junctional RNA scaffolds need to be addressed within such an expanded framework.