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Cif is an epoxide hydrolase that reduces cell-surface abundance of the cystic fibrosis transmembrane conductance regulator (CFTR) and sabotages pro-resolving signals. Its expression is regulated by a divergently transcribed TetR family transcriptional repressor. CifR represents the first reported epoxide-sensing bacterial transcriptional regulator, but neither its interaction with cognate operator sequences nor the mechanism of activation has been investigated. Using biochemical and structural approaches, we uncovered the molecular mechanisms controlling this complex virulence operon. We present here the first molecular structures of CifR alone and in complex with operator DNA, resolved in a single crystal lattice. Significant conformational changes between these two structures suggest how CifR regulates the expression of the virulence gene cif. Interactions between the N-terminal extension of CifR with the DNA minor groove of the operator play a significant role in the operator recognition of CifR. We also determined that cysteine residue Cys107 is critical for epoxide sensing and DNA release. These results offer new insights into the stereochemical regulation of an epoxide-based virulence circuit in a critically important clinical pathogen.<\/jats:p>","DOI":"10.1093\/nar\/gkae889","type":"journal-article","created":{"date-parts":[[2024,10,16]],"date-time":"2024-10-16T17:59:38Z","timestamp":1729101578000},"page":"12727-12747","source":"Crossref","is-referenced-by-count":1,"title":["Molecular basis for the transcriptional regulation of an epoxide-based virulence circuit in <i>Pseudomonas aeruginosa<\/i>"],"prefix":"10.1093","volume":"52","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2138-3421","authenticated-orcid":false,"given":"Susu","family":"He","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Cell Biology, Geisel School of Medicine at Dartmouth , Hanover , NH\u00a0 03755 ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8783-120X","authenticated-orcid":false,"given":"Noor\u00a0M","family":"Taher","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Cell Biology, Geisel School of Medicine at Dartmouth , Hanover , NH\u00a0 03755 ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8175-1196","authenticated-orcid":false,"given":"Adam\u00a0R","family":"Simard","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Cell Biology, Geisel School of Medicine at Dartmouth , Hanover , NH\u00a0 03755 ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4609-6170","authenticated-orcid":false,"given":"Kelli\u00a0L","family":"Hvorecny","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Cell Biology, Geisel School of Medicine at Dartmouth , Hanover , NH\u00a0 03755 ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0231-0876","authenticated-orcid":false,"given":"Michael\u00a0J","family":"Ragusa","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Cell Biology, Geisel School of Medicine at Dartmouth , Hanover , NH\u00a0 03755 ,","place":["USA"]},{"name":"Department of Chemistry , Dartmouth , Hanover , NH\u00a0 03755 ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christopher\u00a0D","family":"Bahl","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Cell Biology, Geisel School of Medicine at Dartmouth , Hanover , NH\u00a0 03755 ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alison\u00a0B","family":"Hickman","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Biology, NIDDK, National Institutes of Health , Bethesda , MD\u00a020892,\u00a0","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fred","family":"Dyda","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Biology, NIDDK, National Institutes of Health , Bethesda , MD\u00a020892,\u00a0","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1810-6984","authenticated-orcid":false,"given":"Dean\u00a0R","family":"Madden","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Cell Biology, Geisel School of Medicine at Dartmouth , Hanover , NH\u00a0 03755 ,","place":["USA"]},{"name":"Department of Chemistry , Dartmouth , Hanover , NH\u00a0 03755 ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2024,10,16]]},"reference":[{"key":"2024111111261356800_B1","doi-asserted-by":"crossref","first-page":"39","DOI":"10.3389\/fcimb.2017.00039","article-title":"Pseudomonas aeruginosa lifestyle: a paradigm for adaptation, survival, and persistence","volume":"7","author":"Moradali","year":"2017","journal-title":"Front. 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Med."},{"key":"2024111111261356800_B4","doi-asserted-by":"crossref","first-page":"e014613","DOI":"10.1136\/bmjopen-2016-014613","article-title":"Pseudomonas aeruginosa isolation in patients with non-cystic fibrosis bronchiectasis: a retrospective study","volume":"8","author":"Wang","year":"2018","journal-title":"BMJ Open"},{"key":"2024111111261356800_B5","first-page":"1602","article-title":"A comprehensive analysis of the impact of Pseudomonas aeruginosa colonization on prognosis in adult bronchiectasis","volume":"12","author":"Finch","year":"2015","journal-title":"Ann Am Thorac Soc"},{"key":"2024111111261356800_B6","doi-asserted-by":"crossref","first-page":"3902","DOI":"10.1128\/IAI.00338-07","article-title":"The Pseudomonas aeruginosa secreted protein PA2934 decreases apical membrane expression of the cystic fibrosis transmembrane conductance regulator","volume":"75","author":"MacEachran","year":"2007","journal-title":"Infect. 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Bacteriol."},{"key":"2024111111261356800_B10","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/j.crstbi.2021.02.002","article-title":"Biochemical and structural characterization of two cif-like epoxide hydrolases from Burkholderia cenocepacia","volume":"3","author":"Taher","year":"2021","journal-title":"Curr Res Struct Biol"},{"key":"2024111111261356800_B11","doi-asserted-by":"crossref","first-page":"9881","DOI":"10.1002\/anie.201503983","article-title":"Inhibiting an epoxide hydrolase virulence factor from Pseudomonas aeruginosa protects CFTR","volume":"54","author":"Bahl","year":"2015","journal-title":"Angew. Chem. Int. 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Chem."},{"key":"2024111111261356800_B15","doi-asserted-by":"crossref","first-page":"L150","DOI":"10.1152\/ajplung.00383.2017","article-title":"An epoxide hydrolase secreted by Pseudomonas aeruginosa decreases mucociliary transport and hinders bacterial clearance from the lung","volume":"314","author":"Hvorecny","year":"2018","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"2024111111261356800_B16","doi-asserted-by":"crossref","first-page":"5315","DOI":"10.1128\/JB.00984-12","article-title":"Epoxide-mediated CifR repression of cif gene expression utilizes two binding sites in Pseudomonas aeruginosa","volume":"194","author":"Ballok","year":"2012","journal-title":"J. Bacteriol."},{"key":"2024111111261356800_B17","doi-asserted-by":"crossref","first-page":"1217","DOI":"10.1111\/j.1432-1033.1991.tb16493.x","article-title":"Characterization of the epoxide hydrolase from an epichlorohydrin-degrading Pseudomonas sp","volume":"202","author":"Jacobs","year":"1991","journal-title":"Eur. J. Biochem."},{"key":"2024111111261356800_B18","doi-asserted-by":"crossref","first-page":"3197","DOI":"10.1128\/IAI.00305-08","article-title":"Cif is negatively regulated by the TetR family repressor CifR","volume":"76","author":"MacEachran","year":"2008","journal-title":"Infect. Immun."},{"key":"2024111111261356800_B19","doi-asserted-by":"crossref","first-page":"S1","DOI":"10.3109\/10409238809083374","article-title":"Methionine biosynthesis in Enterobacteriaceae: biochemical, regulatory, and evolutionary aspects","volume":"23","author":"Saint-Girons","year":"1988","journal-title":"CRC Crit. Rev. 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