scholarly journals Crystal structure of an atypical cobalamin riboswitch reveals RNA structural adaptability as basis for promiscuous ligand binding

2020 ◽  
Author(s):  
Clarence W Chan ◽  
Alfonso Mondragón
Keyword(s):  
Crystal Structure ◽  
Ligand Binding ◽  
Translational Control ◽  
Rna Structure ◽  
Messenger Rna ◽  
Regulatory Elements ◽  
Structural Features ◽  
Functional Coupling ◽  
Expression Platform ◽  
Structural Adaptability

Abstract Cobalamin riboswitches encompass a structurally diverse group of cis-acting, gene regulatory elements found mostly in bacterial messenger RNA and are classified into subtypes based on secondary and tertiary characteristics. An unusual variant of the cobalamin riboswitch with predicted structural features was identified in Bacillus subtilis over a decade ago, but its structure and mechanisms of cobalamin selectivity and translational control have remained unsolved. We present the crystal structure of the aptamer domain of this atypical cobalamin riboswitch and a model for the complete riboswitch, including its expression platform domain. We demonstrate that this riboswitch binds to multiple cobalamin derivatives and correlate its promiscuous behavior to its structure and unique arrangement of peripheral elements. Comparative structural analyses between conventional cobalamin riboswitches and the B. subtilis cobalamin riboswitch reveal that the likely basis for this promiscuous ligand binding is intrinsic structural adaptability encoded in the RNA structure. It suggests that cobalamin selectivity might ultimately be viewed as existing on a spectrum of affinity for each derivative rather than as belonging to distinct types based on ligand specificities. Our work provides an interesting and notable example of functional coupling of ligand-sensing and adaptive folding by a structured RNA molecule.

scholarly journals Crystal Structure of a Mutant hERα Ligand-binding Domain Reveals Key Structural Features for the Mechanism of Partial Agonism

2001 ◽  
Vol 276 (18) ◽  
pp. 15059-15065 ◽  
Author(s):  
Monique Gangloff ◽  
Marc Ruff ◽  
Sylvia Eiler ◽  
Sylvie Duclaud ◽  
Jean Marie Wurtz ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Ligand Binding ◽  
Structural Features ◽  
Binding Domain ◽  
Ligand Binding Domain ◽  
Partial Agonism

scholarly journals Annotating RNA motifs in sequences and alignments

2014 ◽  
Author(s):  
Paul P Gardner ◽  
Hisham Eldai
Keyword(s):  
Rna Structure ◽  
Messenger Rna ◽  
Building Blocks ◽  
Regulatory Elements ◽  
Rna Motifs ◽  
Regulate Gene Expression ◽  
Translational Machinery ◽  
Cellular Life ◽  
Functional Characterisation ◽  
Initial Discovery

RNA performs a diverse array of important functions across all cellular life. These functions include important roles in translation, building translational machinery and maturing messenger RNA. More recent discoveries include the miRNAs and bacterial sRNAs that regulate gene expression, the thermosensors, riboswitches and other cis-regulatory elements that help prokaryotes sense their environment and eukaryotic piRNAs that suppress transposition. However, there can be a long period between the initial discovery of a RNA and determining its function. We present a bioinformatic approach to characterise RNA motifs, which are the central building blocks of RNA structure. These motifs can, in some instances, provide researchers with functional hypotheses for uncharacterised RNAs. Moreover, we introduce a new profile-based database of RNA motifs - RMfam - and illustrate its application for investigating the evolution and functional characterisation of RNA. All the data and scripts associated with this work is available from: https://github.com/ppgardne/RMfam

scholarly journals Structural distinctions between NAD+ riboswitch domains 1 and 2 determine differential folding and ligand binding

2020 ◽  
Vol 48 (21) ◽  
pp. 12394-12406
Author(s):  
Hao Chen ◽  
Michaela Egger ◽  
Xiaochen Xu ◽  
Laurin Flemmich ◽  
Olga Krasheninina ◽  
...  
Keyword(s):  
Gene Regulation ◽  
Ligand Binding ◽  
Regulatory Elements ◽  
Structural Features ◽  
Regulation Mechanism ◽  
Sensor Module ◽  
Binding Pockets ◽  
Gene Regulatory Elements ◽  
Structural Modulation ◽  
Ribosomal Binding Site

Abstract Riboswitches are important gene regulatory elements frequently encountered in bacterial mRNAs. The recently discovered nadA riboswitch contains two similar, tandemly arrayed aptamer domains, with the first domain possessing high affinity for nicotinamide adenine dinucleotide (NAD+). The second domain which comprises the ribosomal binding site in a putative regulatory helix, however, has withdrawn from detection of ligand-induced structural modulation thus far, and therefore, the identity of the cognate ligand and the regulation mechanism have remained unclear. Here, we report crystal structures of both riboswitch domains, each bound to NAD+. Furthermore, we demonstrate that ligand binding to domain 2 requires significantly higher concentrations of NAD+ (or ADP retaining analogs) compared to domain 1. Using a fluorescence spectroscopic approach, we further shed light on the structural features which are responsible for the different ligand affinities, and describe the Mg2+-dependent, distinct folding and pre-organization of their binding pockets. Finally, we speculate about possible scenarios for nadA RNA gene regulation as a putative two-concentration sensor module for a time-controlled signal that is primed and stalled by the gene regulation machinery at low ligand concentrations (domain 1), and finally triggers repression of translation as soon as high ligand concentrations are reached in the cell (domain 2).

scholarly journals Quantitative prediction of variant effects on alternative splicing using endogenous pre-messenger RNA structure probing

2021 ◽  
Author(s):  
Jayashree Kumar ◽  
Lela Lackey ◽  
Justin M. Waldern ◽  
Abhishek Dey ◽  
David H. Mathews ◽  
...  
Keyword(s):  
Rna Structure ◽  
Messenger Rna ◽  
Regulatory Elements ◽  
Quantitative Prediction ◽  
Mrna Structure ◽  
Splicing Regulatory Elements ◽  
Alternatively Spliced ◽  
Endogenous Precursor ◽  
Precursor Mrna

AbstractSplicing is a highly regulated process that depends on numerous factors. It is particularly challenging to quantitatively predict how a mutation will affect precursor messenger RNA (mRNA) structure and the subsequent functional consequences. Here we use a novel Mutational Profiling (-MaP) methodology to obtain highly reproducible endogenous precursor and mature mRNA structural probing data in vivo. We use these data to estimate Boltzmann suboptimal ensembles, and predict the structural consequences of mutations on precursor mRNA structure. Together with a structural analysis of recent cryo-EM spliceosome structures at different stages of the splicing cycle, we determined that the footprint of the Bact complex on precursor mRNA is best able to predict splicing outcomes for exon 10 inclusion of the alternatively spliced MAPT gene. However, structure alone only achieves 74% accuracy. We therefore developed a β-regression weighting framework that incorporates splice site strength, structure and exonic/intronic splicing regulatory elements which together achieves 90% accuracy for 47 known and six newly discovered splice-altering variants. This combined experimental/computational framework represents a path forward for accurate prediction of splicing related disease-causing variants.

scholarly journals Crystal Structure, Exogenous Ligand Binding, and Redox Properties of an Engineered Diiron Active Site in a Bacterial Hemerythrin

2013 ◽  
Vol 52 (22) ◽  
pp. 13014-13020 ◽  
Author(s):  
Yasunori Okamoto ◽  
Akira Onoda ◽  
Hiroshi Sugimoto ◽  
Yu Takano ◽  
Shun Hirota ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Ligand Binding ◽  
Active Site ◽  
Redox Properties ◽  
Exogenous Ligand

scholarly journals The crystal structure of the first ether solvate of hexaphenyldistannane [(Ph3Sn)2 • 2 THF]

2020 ◽  
Vol 43 (1) ◽  
pp. 1-6 ◽  
Author(s):  
Jonathan O. Bauer
Keyword(s):  
Crystal Structure ◽  
Inclusion Compounds ◽  
Molecular Crystal ◽  
Structural Features ◽  
Structural Investigations ◽  
Crystal Solvates

AbstractStructural investigations of molecular crystal solvates can provide important information for the targeted crystallization of particular inclusion compounds. Here, the crystal structure of the first ether solvate of hexaphenyldistannane [(Ph3Sn)2 • 2 THF] is reported. Structural features in terms of host-guest interactions and in the context of the previously reported polymorphs and solvates of (Ph3Sn)2 are discussed.

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