دورية أكاديمية
أعرض في EDS

Toxin release by conditional remodelling of ParDE1 from Mycobacterium tuberculosis leads to gyrase inhibition.

التفاصيل البيبلوغرافية
العنوان: Toxin release by conditional remodelling of ParDE1 from Mycobacterium tuberculosis leads to gyrase inhibition.
المؤلفون: Beck IN; Department of Biosciences, Durham University, South Road, Durham DH1 3LE, UK., Arrowsmith TJ; Department of Biosciences, Durham University, South Road, Durham DH1 3LE, UK., Grobbelaar MJ; Department of Biosciences, Durham University, South Road, Durham DH1 3LE, UK., Bromley EHC; Department of Physics, Durham University, Stockton Road, Durham DH1 3LE, UK., Marles-Wright J; Biosciences Institute, Newcastle University, Framlington Place, Newcastle upon Tyne NE2 4HH, UK., Blower TR; Department of Biosciences, Durham University, South Road, Durham DH1 3LE, UK.
المصدر: Nucleic acids research [Nucleic Acids Res] 2024 Feb 28; Vol. 52 (4), pp. 1909-1929.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: Oxford University Press Country of Publication: England NLM ID: 0411011 Publication Model: Print Cited Medium: Internet ISSN: 1362-4962 (Electronic) Linking ISSN: 03051048 NLM ISO Abbreviation: Nucleic Acids Res Subsets: MEDLINE
أسماء مطبوعة: Publication: 1992- : Oxford : Oxford University Press
Original Publication: London, Information Retrieval ltd.
مواضيع طبية MeSH: Antitoxins*/metabolism , Mycobacterium tuberculosis* , Tuberculosis*/microbiology , Bacterial Toxins*/metabolism, Humans ; Bacterial Proteins/genetics ; Bacterial Proteins/chemistry ; DNA Gyrase/genetics ; Fluoroquinolones ; Pandemics
مستخلص: 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-antitoxin 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-antitoxin 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-antitoxin systems as inspiration for potential therapeutic agents.
(© The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.)
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معلومات مُعتمدة: BB/M011186/1 United Kingdom BB_ Biotechnology and Biological Sciences Research Council
المشرفين على المادة: 0 (Antitoxins)
0 (Bacterial Proteins)
EC 5.99.1.3 (DNA Gyrase)
0 (Fluoroquinolones)
0 (Bacterial Toxins)
تواريخ الأحداث: Date Created: 20231219 Date Completed: 20240229 Latest Revision: 20240301
رمز التحديث: 20240301
مُعرف محوري في PubMed: PMC10899793
DOI: 10.1093/nar/gkad1220
PMID: 38113275
قاعدة البيانات: MEDLINE
الوصف
تدمد:1362-4962
DOI:10.1093/nar/gkad1220