{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T02:24:10Z","timestamp":1784600650073,"version":"3.55.0"},"reference-count":78,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2023,12,19]],"date-time":"2023-12-19T00:00:00Z","timestamp":1702944000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000268","name":"Biotechnology and Biological Sciences Research Council","doi-asserted-by":"publisher","award":["BB\/M011186\/1"],"award-info":[{"award-number":["BB\/M011186\/1"]}],"id":[{"id":"10.13039\/501100000268","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000266","name":"Engineering and Physical Sciences Research Council","doi-asserted-by":"publisher","award":["EP\/S022791\/1"],"award-info":[{"award-number":["EP\/S022791\/1"]}],"id":[{"id":"10.13039\/501100000266","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Biophysical Sciences Institute at Durham University"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,2,28]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Mycobacterium tuberculosis, the causative agent of tuberculosis, is a growing threat to global health, with recent efforts towards its eradication being reversed in the wake of the COVID-19 pandemic. Increasing resistance to gyrase-targeting second-line fluoroquinolone antibiotics indicates the necessity to develop both novel therapeutics and our understanding of M. tuberculosis growth during infection. ParDE toxin\u2013antitoxin systems also target gyrase and are regulated in response to both host-associated and drug-induced stress during infection. Here, we present microbiological, biochemical, structural, and biophysical analyses exploring the ParDE1 and ParDE2 systems of M. tuberculosis H37Rv. The structures reveal conserved modes of toxin\u2013antitoxin recognition, with complex-specific interactions. ParDE1 forms a novel heterohexameric ParDE complex, supported by antitoxin chains taking on two distinct folds. Curiously, ParDE1 exists in solution as a dynamic equilibrium between heterotetrameric and heterohexameric complexes. Conditional remodelling into higher order complexes can be thermally driven in vitro. Remodelling induces toxin release, tracked through concomitant inhibition and poisoning of gyrase activity. Our work aids our understanding of gyrase inhibition, allowing wider exploration of toxin\u2013antitoxin systems as inspiration for potential therapeutic agents.<\/jats:p>","DOI":"10.1093\/nar\/gkad1220","type":"journal-article","created":{"date-parts":[[2023,12,19]],"date-time":"2023-12-19T18:38:44Z","timestamp":1703011124000},"page":"1909-1929","source":"Crossref","is-referenced-by-count":14,"title":["Toxin release by conditional remodelling of ParDE1 from <i>Mycobacterium tuberculosis<\/i> leads to gyrase inhibition"],"prefix":"10.1093","volume":"52","author":[{"given":"Izaak N","family":"Beck","sequence":"first","affiliation":[{"name":"Department of Biosciences, Durham University , South Road , Durham DH1 3LE , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-9079-9973","authenticated-orcid":false,"given":"Tom J","family":"Arrowsmith","sequence":"additional","affiliation":[{"name":"Department of Biosciences, Durham University , South Road , Durham DH1 3LE , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4124-2949","authenticated-orcid":false,"given":"Matthew J","family":"Grobbelaar","sequence":"additional","affiliation":[{"name":"Department of Biosciences, Durham University , South Road , Durham DH1 3LE , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth\u00a0H C","family":"Bromley","sequence":"additional","affiliation":[{"name":"Department of Physics, Durham University , Stockton Road , Durham DH1 3LE , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jon","family":"Marles-Wright","sequence":"additional","affiliation":[{"name":"Biosciences Institute, Newcastle University , Framlington Place, Newcastle upon Tyne NE2 4HH , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7390-6458","authenticated-orcid":false,"given":"Tim R","family":"Blower","sequence":"additional","affiliation":[{"name":"Department of Biosciences, Durham University , South Road , Durham DH1 3LE , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2023,12,19]]},"reference":[{"key":"2024022807084695800_B1","article-title":"Global Tuberculosis Report 2022","author":"World Health Organisation","year":"2022"},{"key":"2024022807084695800_B2","doi-asserted-by":"crossref","first-page":"E839","DOI":"10.1073\/pnas.1525055113","article-title":"Fluoroquinolone interactions with Mycobacterium tuberculosis gyrase: enhancing drug activity against wild-type and resistant gyrase","volume":"113","author":"Aldred","year":"2016","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2024022807084695800_B3","doi-asserted-by":"crossref","first-page":"1706","DOI":"10.1073\/pnas.1525047113","article-title":"Crystal structure and stability of gyrase-fluoroquinolone cleaved complexes from Mycobacterium tuberculosis","volume":"113","author":"Blower","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2024022807084695800_B4","doi-asserted-by":"crossref","first-page":"510","DOI":"10.1016\/j.drudis.2016.11.006","article-title":"DNA topoisomerase I and DNA gyrase as targets for TB therapy","volume":"22","author":"Nagaraja","year":"2017","journal-title":"Drug Discov. Today"},{"key":"2024022807084695800_B5","doi-asserted-by":"crossref","first-page":"827","DOI":"10.1038\/nrm3228","article-title":"All tangled up: how cells direct, manage and exploit topoisomerase function","volume":"12","author":"Vos","year":"2011","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"2024022807084695800_B6","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1017\/S0033583598003424","article-title":"Moving one DNA double helix through another by a type II DNA topoisomerase: the story of a simple molecular machine","volume":"31","author":"Wang","year":"1998","journal-title":"Q. Rev. Biophys."},{"key":"2024022807084695800_B7","doi-asserted-by":"crossref","first-page":"3427","DOI":"10.1016\/j.jmb.2019.07.008","article-title":"DNA topoisomerase inhibitors: trapping a DNA-cleaving machine in motion","volume":"431","author":"Bax","year":"2019","journal-title":"J. Mol. Biol."},{"key":"2024022807084695800_B8","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1021\/cb300648v","article-title":"Drugging Topoisomerases: lessons and Challenges","volume":"8","author":"Pommier","year":"2013","journal-title":"ACS Chem. Biol."},{"key":"2024022807084695800_B9","doi-asserted-by":"crossref","first-page":"2401","DOI":"10.1042\/BCJ20200368","article-title":"Antitoxin autoregulation of M. tuberculosis toxin\u2013antitoxin expression through negative cooperativity arising from multiple inverted repeat sequences","volume":"477","author":"Beck","year":"2020","journal-title":"Biochem. J."},{"key":"2024022807084695800_B10","doi-asserted-by":"crossref","first-page":"894","DOI":"10.1073\/pnas.0808832106","article-title":"The phage abortive infection system, ToxIN, functions as a protein-RNA toxin\u2013antitoxin pair","volume":"106","author":"Fineran","year":"2009","journal-title":"Proc. Natl. Acad. Sci. 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