This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Recent studies have shown that gene expression in both prokaryotes and eukaryotes can be controlled through interactions of mRNA elements, called riboswitches, with small cellular metabolites, such as coenzymes, sugars, amino acids and nucleobases. Riboswitches are typically composed of two regions. The first region forms evolutionary conserved and independently folded metabolite-binding domain, specific for a certain metabolite. The second region, non-conserved expression platform, carries gene expression signals. The conformational transitions associated with metabolite binding are interpreted through the expression platforms which regulate gene expression by typically translational or transcriptional attenuation. Our research efforts are focused on the determination of the three-dimensional structures of the riboswitch metabolite-sensing modules in the free and bound states, towards an improved understanding of the conformational transitions harnessed by the expression platforms for allosteric modulation of gene expression. These studies will uncover the molecular mechanisms dictating riboswitch function and will help in the evaluation of riboswitches as novel antimicrobial drug targets. Among several riboswitch classes, amino acid specific riboswitches have not been structurally characterized. Despite the fact that many amino acids can be specifically recognized by RNA on the RNA-protein interfaces, these riboswitches should adapt conformations different from the protein-binding RNA structures, because riboswitches can distinguish a single amino acid among many other natural amino acids, their precursors, and amino acids in the peptide context. The riboswitch specific to amino acid lysine (174-nt in length) is also distinct from earlier riboswitches (app. 70-nt in length), given its much larger size and multi-stem junctional secondary fold.
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