Roseoflavin is a natural antibacterial compound that binds to FMN riboswitches and regulates gene expression

Lee, Elaine R.; Blount, Ken; Breaker, Ronald R.

doi:10.4161/rna.6.2.7727

Cited by 216 publications

(194 citation statements)

References 39 publications

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“…The secondary structure of this sequence, which depends on the presence or absence of the ligand, directs the folding of the rest of the expression platform into two mutually exclusive forms that represent the on and off states of the mRNA (Garst et al 2011;Batey 2012;Serganov and Patel 2012). The active role that riboswitches play in regulating bacterial transcription makes them enticing targets for development of novel antibiotics, and several drug-like small molecules have been found to bind to riboswitches and slow cell growth (Sudarsan et al 2005;Blount et al 2007; Lee et al 2009). …”

Section: Introductionmentioning

confidence: 99%

Loop–loop interaction in an adenine-sensing riboswitch: A molecular dynamics study

Allnér

Nilsson

Villa

2013

RNA

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Riboswitches are mRNA-based molecules capable of controlling the expression of genes. They undergo conformational changes upon ligand binding, and as a result, they inhibit or promote the expression of the associated gene. The close connection between structural rearrangement and function makes a detailed knowledge of the molecular interactions an important step to understand the riboswitch mechanism and efficiency. We have performed all-atom molecular dynamics simulations of the adenine-sensing add A-riboswitch to study the breaking of the kissing loop, one key tertiary element in the aptamer structure. We investigated the aptamer domain of the add A-riboswitch in complex with its cognate ligand and in the absence of the ligand. The opening of the hairpins was simulated using umbrella sampling using the distance between two loops as the reaction coordinate. A two-step process was observed in all the simulated systems. First, a general loss of stacking and hydrogen bond interactions is seen. The last interactions that break are the two base pairs G37-C61 and G38-C60, but the break does not affect the energy profile, indicating their pivotal role in the tertiary structure formation but not in the structure stabilization. The junction area is partially organized before the kissing loop formation and residue A24 anchors together the loop helices. Moreover, when the distance between the loops is increased, one of the hairpins showed more flexibility by changing its orientation in the structure, while the other conserved its coaxial arrangement with the rest of the structure.

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Section: Introductionmentioning

confidence: 99%

Loop–loop interaction in an adenine-sensing riboswitch: A molecular dynamics study

Allnér

Nilsson

Villa

2013

RNA

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“…Riboswitches appear capable of manipulating the expression of genes related to metabolite biosynthesis without direct interaction with proteins. Moreover, riboswitches have been suggested as potential drug targets (Blount and Breaker 2006;Blount et al 2007;Kim et al 2009;Lee et al 2009;Cressina et al 2011;Daldrop et al 2011;Deigan and Ferré-D'Amaré 2011;Maciagiewicz et al 2011) and for a number of potential engineering applications (Wieland and Hartig 2008;Link and Breaker 2009;Topp and Gallivan 2010), highlighting the importance of understanding mechanisms for specificity and recognition of riboswitches by small molecule ligands Haller et al 2011).…”

Section: Introductionmentioning

confidence: 99%

Basis for ligand discrimination between ON and OFF state riboswitch conformations: The case of the SAM-I riboswitch

Boyapati¹,

Huang²,

Spedale³

et al. 2012

RNA

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Riboswitches are RNA elements that bind to effector ligands and control gene expression. Most consist of two domains. S-Adenosyl Methionine (SAM) binds the aptamer domain of the SAM-I riboswitch and induces conformational changes in the expression domain to form an intrinsic terminator (transcription OFF state). Without SAM the riboswitch forms the transcription ON state, allowing read-through transcription. The mechanistic link between the SAM/aptamer recognition event and subsequent secondary structure rearrangement by the riboswitch is unclear. We probed for those structural features of the Bacillus subtilis yitJ SAM-I riboswitch responsible for discrimination between the ON and OFF states by SAM. We designed SAM-I riboswitch RNA segments forming ''hybrid'' structures of the ON and OFF states. The choice of segment constrains the formation of a partial P1 helix, characteristic of the OFF state, together with a partial antiterminator (AT) helix, characteristic of the ON state. For most choices of P1 vs. AT helix lengths, SAM binds with micromolar affinity according to equilibrium dialysis. Mutational analysis and in-line probing confirm that the mode of SAM binding by hybrid structures is similar to that of the aptamer. Altogether, binding measurements and in-line probing are consistent with the hypothesis that when SAM is present, stacking interactions with the AT helix stabilize a partially formed P1 helix in the hybrids. Molecular modeling indicates that continuous stacking between the P1 and the AT helices is plausible with SAM bound. Our findings raise the possibility that conformational intermediates may play a role in ligand-induced aptamer folding.

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“…Although present in all domains of life, they are prominent in bacteria where they typically reside in the 5′-leader sequences of mRNA (2). Broad interest in riboswitches originates from the discovery that they can be targeted by antimicrobials (3)(4)(5), and the observation that they use complex scaffolds to achieve gene regulation without the need for protein partners. In the latter respect, riboswitches typically exhibit bipartite sequence organization comprising a conserved aptamer linked to a downstream expression platform (2).…”

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confidence: 99%

Structural analysis of a class III preQ ₁ riboswitch reveals an aptamer distant from a ribosome-binding site regulated by fast dynamics

Liberman

Suddala

Aytenfisu

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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PreQ 1 -III riboswitches are newly identified RNA elements that control bacterial genes in response to preQ 1 (7-aminomethyl-7-deazaguanine), a precursor to the essential hypermodified tRNA base queuosine. Although numerous riboswitches fold as H-type or HL out -type pseudoknots that integrate ligand-binding and regulatory sequences within a single folded domain, the preQ 1 -III riboswitch aptamer forms a HL out -type pseudoknot that does not appear to incorporate its ribosome-binding site (RBS). To understand how this unusual organization confers function, we determined the crystal structure of the class III preQ 1 riboswitch from Faecalibacterium prausnitzii at 2.75 Å resolution. PreQ 1 binds tightly (K D,app 6.5 ± 0.5 nM) between helices P1 and P2 of a three-way helical junction wherein the third helix, P4, projects orthogonally from the ligand-binding pocket, exposing its stem-loop to base pair with the 3′ RBS. Biochemical analysis, computational modeling, and single-molecule FRET imaging demonstrated that preQ 1 enhances P4 reorientation toward P1-P2, promoting a partially nested, H-type pseudoknot in which the RBS undergoes rapid docking (k dock ∼0.6 s −1 ) and undocking (k undock ∼1.1 s −1 ). Discovery of such dynamic conformational switching provides insight into how a riboswitch with bipartite architecture uses dynamics to modulate expression platform accessibility, thus expanding the known repertoire of gene control strategies used by regulatory RNAs. preQ 1 riboswitch | gene regulation | crystal structure | single-molecule FRET | molecular dynamics R iboswitches are structured RNA motifs that sense the cellular levels of small molecules to provide feedback regulation of genes (1). Although present in all domains of life, they are prominent in bacteria where they typically reside in the 5′-leader sequences of mRNA (2). Broad interest in riboswitches originates from the discovery that they can be targeted by antimicrobials (3-5), and the observation that they use complex scaffolds to achieve gene regulation without the need for protein partners. In the latter respect, riboswitches typically exhibit bipartite sequence organization comprising a conserved aptamer linked to a downstream expression platform (2). Aptamer binding to a cognate effector can induce conformational changes that alter the accessibility of expression platform sequences, such as those required for transcriptional read-through, or hybridization to the 16S rRNA as a preface to translation (2, 6).Numerous riboswitches fold as pseudoknots that conform to the H-type or closely related HL out -type topology, which have emerged as the most efficient RNA scaffolds to integrate aptamer and expression platform sequences (7). The preQ 1 -I, preQ 1 -II, S-adenosyl-L-methionine-II (SAM-II), and fluoride riboswitches are representative of this organizational strategy, and their analysis has contributed to a renaissance in our understanding of regulatory pseudoknot structure and dynamics (8-18). By contrast, pseudoknotted aptamers that do not integr...

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Roseoflavin is a natural antibacterial compound that binds to FMN riboswitches and regulates gene expression

Cited by 216 publications

References 39 publications

Loop–loop interaction in an adenine-sensing riboswitch: A molecular dynamics study

Loop–loop interaction in an adenine-sensing riboswitch: A molecular dynamics study

Basis for ligand discrimination between ON and OFF state riboswitch conformations: The case of the SAM-I riboswitch

Structural analysis of a class III preQ ₁ riboswitch reveals an aptamer distant from a ribosome-binding site regulated by fast dynamics

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Roseoflavin is a natural antibacterial compound that binds to FMN riboswitches and regulates gene expression

Cited by 216 publications

References 39 publications

Loop–loop interaction in an adenine-sensing riboswitch: A molecular dynamics study

Loop–loop interaction in an adenine-sensing riboswitch: A molecular dynamics study

Basis for ligand discrimination between ON and OFF state riboswitch conformations: The case of the SAM-I riboswitch

Structural analysis of a class III preQ 1 riboswitch reveals an aptamer distant from a ribosome-binding site regulated by fast dynamics

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Structural analysis of a class III preQ ₁ riboswitch reveals an aptamer distant from a ribosome-binding site regulated by fast dynamics