{"doi":"10.1093/nar/gkt798","title":"Single transcriptional and translational preQ1 riboswitches adopt similar pre-folded ensembles that follow distinct folding pathways into the same ligand-bound structure","abstract":"<jats:title>Abstract</jats:title>\n               <jats:p>Riboswitches are structural elements in the 5′ untranslated regions of many bacterial messenger RNAs that regulate gene expression in response to changing metabolite concentrations by inhibition of either transcription or translation initiation. The preQ1 (7-aminomethyl-7-deazaguanine) riboswitch family comprises some of the smallest metabolite sensing RNAs found in nature. Once ligand-bound, the transcriptional Bacillus subtilis and translational Thermoanaerobacter tengcongensis preQ1 riboswitch aptamers are structurally similar RNA pseudoknots; yet, prior structural studies have characterized their ligand-free conformations as largely unfolded and folded, respectively. In contrast, through single molecule observation, we now show that, at near-physiological Mg2+ concentration and pH, both ligand-free aptamers adopt similar pre-folded state ensembles that differ in their ligand-mediated folding. Structure-based Gō-model simulations of the two aptamers suggest that the ligand binds late (Bacillus subtilis) and early (Thermoanaerobacter tengcongensis) relative to pseudoknot folding, leading to the proposal that the principal distinction between the two riboswitches lies in their relative tendencies to fold via mechanisms of conformational selection and induced fit, respectively. These mechanistic insights are put to the test by rationally designing a single nucleotide swap distal from the ligand binding pocket that we find to predictably control the aptamers′ pre-folded states and their ligand binding affinities.</jats:p>","journal":"Nucleic Acids Research","year":2013,"id":679825,"datarank":0.692268077526189,"base_score":4.61512051684126,"endowment":4.61512051684126,"self_citation_contribution":0.692268077526189,"citation_network_contribution":0.0,"self_endowment_contribution":0.692268077526189,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":100,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1776260,"name":"Arlie J. Rinaldi","orcid":null,"position":1,"is_corresponding":false},{"id":1322329,"name":"Jun Feng","orcid":"0000-0001-5730-3844","position":2,"is_corresponding":false},{"id":295952,"name":"Anthony M. Mustoe","orcid":"0000-0001-9346-1559","position":3,"is_corresponding":false},{"id":379032,"name":"Catherine D. Eichhorn","orcid":"0000-0001-8624-1961","position":4,"is_corresponding":false},{"id":1776261,"name":"Joseph A. Liberman","orcid":null,"position":5,"is_corresponding":false},{"id":467934,"name":"Joseph E. Wedekind","orcid":"0000-0002-4269-4229","position":6,"is_corresponding":false},{"id":1776264,"name":"Hashim M. Al-Hashimi","orcid":null,"position":7,"is_corresponding":false},{"id":141430,"name":"Charles L. Brooks","orcid":null,"position":8,"is_corresponding":false},{"id":260371,"name":"Nils G. Walter","orcid":"0000-0002-7301-1275","position":9,"is_corresponding":false},{"id":1071689,"name":"Krishna C. Suddala","orcid":"0000-0003-1597-2622","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Single transcriptional and translational preQ1 riboswitches adopt similar pre-folded ensembles that follow distinct folding pathways into the same ligand-bound structure","abstract":"<jats:title>Abstract</jats:title>\n               <jats:p>Riboswitches are structural elements in the 5′ untranslated regions of many bacterial messenger RNAs that regulate gene expression in response to changing metabolite concentrations by inhibition of either transcription or translation initiation. The preQ1 (7-aminomethyl-7-deazaguanine) riboswitch family comprises some of the smallest metabolite sensing RNAs found in nature. Once ligand-bound, the transcriptional Bacillus subtilis and translational Thermoanaerobacter tengcongensis preQ1 riboswitch aptamers are structurally similar RNA pseudoknots; yet, prior structural studies have characterized their ligand-free conformations as largely unfolded and folded, respectively. In contrast, through single molecule observation, we now show that, at near-physiological Mg2+ concentration and pH, both ligand-free aptamers adopt similar pre-folded state ensembles that differ in their ligand-mediated folding. Structure-based Gō-model simulations of the two aptamers suggest that the ligand binds late (Bacillus subtilis) and early (Thermoanaerobacter tengcongensis) relative to pseudoknot folding, leading to the proposal that the principal distinction between the two riboswitches lies in their relative tendencies to fold via mechanisms of conformational selection and induced fit, respectively. These mechanistic insights are put to the test by rationally designing a single nucleotide swap distal from the ligand binding pocket that we find to predictably control the aptamers′ pre-folded states and their ligand binding affinities.</jats:p>","is_dataset_classified":null,"base_score":4.61512051684126,"endowment":4.61512051684126,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"24003028","pmcid":null,"openalex_id":"https://openalex.org/W2063442684","authors":[],"funders":[{"funder_name":"National Institutes of Health","grant_id":"5R21GM096156-02","title":"Dynamic Structures of Large and Flexible RNAs"},{"funder_name":"NIGMS NIH HHS","grant_id":"GM062357","title":null},{"funder_name":"NIGMS NIH HHS","grant_id":"GM063162","title":null},{"funder_name":"NIGMS NIH HHS","grant_id":"T32 GM068411","title":null},{"funder_name":"NCRR NIH HHS","grant_id":"P41 RR012255","title":null},{"funder_name":"NIGMS NIH HHS","grant_id":"R01 GM063162","title":null},{"funder_name":"NCRR NIH HHS","grant_id":"RR012255","title":null},{"funder_name":"NIGMS NIH HHS","grant_id":"R21GM096156","title":null}],"total_grants":8,"fwci":4.947,"citation_percentile":0.96223757,"influential_citations":4,"citation_trend":[{"year":2014,"count":22},{"year":2015,"count":6},{"year":2016,"count":8},{"year":2017,"count":6},{"year":2018,"count":10},{"year":2019,"count":7},{"year":2020,"count":2},{"year":2021,"count":8},{"year":2022,"count":7},{"year":2023,"count":6},{"year":2024,"count":9},{"year":2025,"count":5},{"year":2026,"count":4}],"oa_status":"gold","license":"cc-by","oa_locations":[{"url":"https://doi.org/10.1093/nar/gkt798","host_type":"journal"},{"url":"https://doi.org/10.1093/nar/gkt798","host_type":"GOLD"},{"url":"https://doi.org/10.1093/nar/gkt798","host_type":"publisher"},{"url":"https://academic.oup.com/nar/article-pdf/41/22/10462/59481891/nar_41_22_10462.pdf","host_type":"publisher"},{"url":"https://pubmed.ncbi.nlm.nih.gov/24003028","host_type":"repository"},{"url":"http://europepmc.org/articles/PMC3905878","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/3905878","host_type":"repository"},{"url":"https://digitalcommons.unl.edu/chemfacpub/179","host_type":"repository"},{"url":"http://dx.doi.org/10.1093/nar/gkt798","host_type":""},{"url":"https://dx.doi.org/10.1093/nar/gkt798","host_type":""}],"fields_of_study":["RNA and protein synthesis mechanisms","RNA modifications and cancer","RNA Research and Splicing","Biology","Medicine","Chemistry","0301 basic medicine","0303 health sciences","03 medical and health sciences","Bacillus subtilis","Fluorescence Resonance Energy Transfer","Ligands","Nucleic Acid Conformation","Protein Biosynthesis","Pyrimidinones","Pyrroles","RNA Folding","Riboswitch","Thermoanaerobacter","Transcription, Genetic"],"mesh_terms":["Bacillus subtilis","Ligands","Nucleic Acid Conformation","Pyrimidinones","Pyrroles","Transcription, Genetic","Protein Biosynthesis","Fluorescence Resonance Energy Transfer","Thermoanaerobacter","Riboswitch","RNA Folding"],"keywords":["Biology","Riboswitch","Folding (DSP implementation)","Computational biology","Pseudoknot","Protein folding","RNA","Biophysics","Cell biology","Bioinformatics","Genetics","Gene","Non-coding RNA","570","RNA Folding","Transcription, Genetic","Medicinal-Pharmaceutical Chemistry","Thermoanaerobacter","Pyrimidinones","Ligands","Analytical Chemistry","Chemistry","Protein Biosynthesis","Physical Sciences and Mathematics","Fluorescence Resonance Energy Transfer","Nucleic Acid Conformation","Other Chemistry","Pyrroles","Bacillus subtilis"],"sdg_mappings":[{"sdg_number":0,"sdg_label":"Life in Land"}],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-17T13:52:42.404791Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}