Targeting the Riboswitch

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Recent research has shown that gene expression can be regulated at the level of mRNA by riboswitches. A riboswitch is an aptamer region on an mRNA molecule that can specifically bind a small effector molecule, causing changes in the structure of the expression platform and so regulating the activity of the mRNA. Riboswitches most usually switch off the ability of mRNA to carry out protein synthesis but can also switch it on. A variety of riboswitch classes have been identified, with most of the examples being discovered in bacteria including E. coli and streptococcus as well as bacteria causing anthrax, gonorrhoea, meningitis and dysentry.

Crystal structure of preQ1 riboswitchResearchers at the University of Rochester Medical Center have now solved the crystal structure of the smallest known riboswitch, the preQ1 riboswitch. The preQ1 riboswitch controls the ability of bacteria to produce queuosine (Q), a molecule which enables accurate gene expression by overcoming an inbuilt defect in the mRNA-ribosome-tRNA system known as tRNA wobble, and which is essential for the survival of many important pathological bacteria. The preQ1 riboswitch ‘senses’ the level of preQ1, a precursor to Q. If too much preQ1 is present, genes responsible for producing preQ1, or for its transport, are shut down. The preQ1 precursor, known as preQ0, has the same effect in reducing production of Q. One gene that is regulated by the preQ1 riboswitch is that which codes for the enzyme queF, which converts preQ0 into preQ1.

The structure of the preQ1 riboswitch from Thermoanaerobacter tengcongensis complexed with preQ0 shows preQ0 bound in a buried pocket. The structure also reveals how the first base of the mRNA ribosome binding site binds to a loop of the riboswitch, and how the loop end of the preQ1 riboswitch aptamer domain binds to preQ0. Binding of the preQ1 aptamer loop to the first base in the ribosome binding site was found to be mediated by a standard G to C base pairing interaction. The preQ1 aptamer (34 nucleotides) is about 2.5-fold shorter than functionally related riboswitches that recognize similar metabolites.

An understanding of how bacterial species sequester their ribosome binding sites using divergent preQ1 riboswitch aptamers could lead to the design of a new class of antibiotics. There is evidence that some existing antibiotics act – in part at least – by targeting riboswitches and, since riboswitches have not yet been found in human cells, the hope is that antibiotics acting on riboswitches will have a low propensity for side effects. The study is published in the Journal of Biological Chemistry.


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