High Affinity Binding of N2-Modified Guanine Derivatives Significantly Disrupts the Ligand Binding Pocket of the Guanine Riboswitch.

Riboswitches are important model systems for the development of approaches to search for RNA-targeting therapeutics. A principal challenge in finding compounds that target riboswitches is that the effector ligand is typically almost completely encapsulated by the RNA, which severely limits the chemical space that can be explored. Efforts to find compounds that bind the guanine/adenine class of riboswitches with a high affinity have in part focused on purines modified at the C6 and C2 positions.

Structural basis for 2'-deoxyguanosine recognition by the 2'-dG-II class of riboswitches.

A recent bioinformatic analysis of well-characterized classes of riboswitches uncovered subgroups unable to bind to the regulatory molecule of the parental class. Within the guanine/adenine class, seven groups of RNAs were identified that deviate from the consensus sequence at one or more of three positions directly involved purine nucleobase recognition, one of which was validated as a second class of 2'-deoxyguanosine riboswitch (called 2'-dG-II). To understand how 2'-dG-II riboswitches recognize their cognate ligand and how they differ from a previously identified class of 2'-deoxyguanosine binding riboswitches, we have solved the crystal structure of a 2'-dG-II aptamer domain bound to 2'-deoxyguanosine.

Metal Ion-Mediated Nucleobase Recognition by the ZTP Riboswitch.

The ZTP riboswitch is a widespread family of regulatory RNAs that upregulate de novo purine synthesis in response to increased intracellular levels of ZTP or ZMP. As an important intermediate in purine biosynthesis, ZMP also serves as a proxy for the concentration of N10-formyl-tetrahydrofolate, a key component of one-carbon metabolism. Here, we report the structure of the ZTP riboswitch bound to ZMP at a resolution of 1.

Methionine increases BDNF DNA methylation and improves memory in epilepsy.

Objective: Temporal lobe epilepsy (TLE) patients exhibit signs of memory impairments even when seizures are pharmacologically controlled. Surprisingly, the underlying molecular mechanisms involved in TLE-associated memory impairments remain elusive. Memory consolidation requires epigenetic transcriptional regulation of genes in the hippocampus; therefore, we aimed to determine how epigenetic DNA methylation mechanisms affect learning-induced transcription of memory-permissive genes in the epileptic hippocampus.