دورية أكاديمية
أعرض في EDS

Modeling allosteric mechanisms of eukaryotic type II topoisomerases.

التفاصيل البيبلوغرافية
العنوان: Modeling allosteric mechanisms of eukaryotic type II topoisomerases.
المؤلفون: Evoli S; Department of Physics, Illinois Institute of Technology, Chicago, Illinois; Center for Molecular Study of Condensed Soft Matter, Illinois Institute of Technology, Chicago, Illinois., Kariyawasam NL; Department of Physics, Illinois Institute of Technology, Chicago, Illinois; Center for Molecular Study of Condensed Soft Matter, Illinois Institute of Technology, Chicago, Illinois., Nitiss KC; Pharmaceutical Sciences Department, University of Illinois at Chicago, Rockford, Illinois., Nitiss JL; Pharmaceutical Sciences Department, University of Illinois at Chicago, Rockford, Illinois., Wereszczynski J; Department of Physics, Illinois Institute of Technology, Chicago, Illinois; Center for Molecular Study of Condensed Soft Matter, Illinois Institute of Technology, Chicago, Illinois; Department of Biology, Illinois Institute of Technology, Chicago, Illinois. Electronic address: jwereszc@iit.edu.
المصدر: Biophysical journal [Biophys J] 2024 Jun 18; Vol. 123 (12), pp. 1620-1634. Date of Electronic Publication: 2024 May 08.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: Cell Press Country of Publication: United States NLM ID: 0370626 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1542-0086 (Electronic) Linking ISSN: 00063495 NLM ISO Abbreviation: Biophys J Subsets: MEDLINE
أسماء مطبوعة: Publication: Cambridge, MA : Cell Press
Original Publication: New York, Published by Rockefeller University Press [etc.] for the Biophysical Society.
مواضيع طبية MeSH: DNA Topoisomerases, Type II*/metabolism , DNA Topoisomerases, Type II*/chemistry , DNA Topoisomerases, Type II*/genetics , Molecular Dynamics Simulation*, Allosteric Regulation ; Saccharomyces cerevisiae/enzymology ; Saccharomyces cerevisiae/metabolism ; Protein Domains ; Models, Molecular
مستخلص: Type II topoisomerases (TopoIIs) are ubiquitous enzymes that are involved in crucial nuclear processes such as genome organization, chromosome segregation, and other DNA metabolic processes. These enzymes function as large, homodimeric complexes that undergo a complex cycle of binding and hydrolysis of two ATP molecules in their ATPase domains, which regulates the capture and passage of one DNA double-helix through a second, cleaved DNA molecule. This process requires the transmission of information about the state of the bound nucleotide over vast ranges in the TopoII complex. How this information is transmitted at the molecular level to regulate TopoII functions and how protein substitutions disrupt these mechanisms remains largely unknown. Here, we employed extensive microsecond-scale molecular dynamics simulations of the yeast TopoII enzyme in multiple nucleotide-bound states and with amino acid substitutions near both the N and C termini of the complex. Simulation results indicate that the ATPase domains are remarkably flexible on the sub-microsecond timescale and that these dynamics are modulated by the identity of the bound nucleotides and both local and distant amino acid substitutions. Network analyses point toward specific allosteric networks that transmit information about the hydrolysis cycle throughout the complex, which include residues in both the protein and the bound DNA molecule. Amino acid substitutions weaken many of these pathways. Together, our results provide molecular level details on how the TopoII catalytic cycle is controlled through nucleotide binding and hydrolysis and how mutations may disrupt this process.
Competing Interests: Declaration of interests The authors declare no competing interests.
(Copyright © 2024 Biophysical Society. Published by Elsevier Inc. All rights reserved.)
التعليقات: Update of: bioRxiv. 2024 Mar 24:2023.08.02.551689. doi: 10.1101/2023.08.02.551689. (PMID: 37577673)
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المشرفين على المادة: EC 5.99.1.3 (DNA Topoisomerases, Type II)
تواريخ الأحداث: Date Created: 20240509 Date Completed: 20240619 Latest Revision: 20240701
رمز التحديث: 20240701
مُعرف محوري في PubMed: PMC11213992
DOI: 10.1016/j.bpj.2024.05.004
PMID: 38720465
قاعدة البيانات: MEDLINE
الوصف
تدمد:1542-0086
DOI:10.1016/j.bpj.2024.05.004