topoisomerase ii structure
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topoisomerase ii structure

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Then, it passes the other DNA through the gap, resolving the tangle. Synthesis and structure of [(η6-p-cymene)Ru(2-anthracen-9 ... Maxwell A. Dodson G. Crystal structure of an N-terminal fragment of the DNA gyrase B . Structure Topoisomerase I is a monomer. HIV-1-associated Topoisomerase II beta kinase (TopoIIβKHIV-1) phosphorylates host . Therefore, we conclude that the human Top2β crystal structure in complex with etoposide is a good template for homology modelling in the context of virtual . A role of topoisomerase II in linking DNA replication to ... Because it cuts both strands of DNA, it is considered to be a Class II topoisomerase. Investigation of Structure-Activity Relationships of ... Crystal structure of human topoisomerase II beta in complex with 5-iodouridine-containing-DNA and etoposide in space group p21 DOI: 10.2210/pdb5ZRF/pdb NDB: 5ZRF Novel DNA Topoisomerase IIα Inhibitors from Combined ... Structure of the topoisomerase II ATPase region and its ... This structure contains DNA cleavage core of Top2-α bound to a doubly nicked, 30-bp duplex oligonucleotide (Wendorff et al., 2012). In the case of topoisomerase II, however, two different openings are involved, one to allow entrance . In order to manage the DNA tangles and supercoils, the type II topoisomerase cut both the DNA strands simultaneously. Training. Etoposide, Mitoxantrone and Amsacrine . They need ATP hydrolyzing for this activity. TABLE1 of Human Topoisomerase II . [PMC free article] [Google Scholar] 110. Compounds (22-25) which contain hydroxyl group at meta position of the 2-phenyl ring at 2-position and furanyl or thienyl substitution at 4-position of indenopyridine, showed . For each structure, selected residues from the enclosed region are shown in an enlarged view . Partial digestion of β with either trypsin or protease SV8 generated fragments . Importantly, we found that TOP2 deficiency in both yeast and . winding due to double helical structure of DNA, topoi-somerases attach to single or double stranded DNA, which makes single stranded nicks to relax the helix, and relive the topological tension (removing DNA supercoil-ing) 15. About us. I. Three-Domain Structure of Topoisomerase II. Furthermore, cell extracts from DmSMC4 dsRNA-treated cells show significantly reduced topoisomerase II-dependent DNA decatenation activity in vitro. Moreover, the three main subclasses of topoisomerase I are Type IA topoisomerase, Type IB topoisomerase, and . The x-ray crystal structure of the [Cu(PTZ-tBTSC)Cl] complex shows that the complex adopts a square planar arrangement around the copper(II) ion, but forms a sulfur-bridged dimer in the solid state. The Structure of DNA-Bound Human Topoisomerase II Alpha: Conformational Mechanisms for Coordinating Inter-Subunit Interactions with DNA Cleavage Timothy J. Wendorff1, Bryan H. Schmidt2, Pauline . Here we present the structure of a fully catalytic Saccharomyces cerevisiae topoisomerase II homodimer complexed with DNA and a nonhydrolyzable ATP analog. Topoisomerase II (topo II), which catalyzes a transient breakage and reunion of double-stranded DNA, was the first protein shown to be essential for mitotic chromosome condensation (Uemura et al., 1987).A role for topo II in the structural maintenance of mitotic chromosomes has been suggested on the basis of the finding that topo II is a major constituent of the chromosome scaffold (Earnshaw . Recombinant human topoisomerase IIβ (residues 46-1621 fused to the first 5 residues of yeast topoisomerase II) was purified to homogeneity, yielding an enzymatically active polypeptide in sufficient quantity to allow analysis of its domain structure and comparison with that of recombinant human topoisomerase IIα. Topoisomerase cuts DNA at a particular point and unravels the twist in order to relieve the supercoil. Additionally, topoisomerase-II is dimeric or tetrameric because it has to work on breaking and ligating both strands of DNA. Type II topoisomerases are topoisomerases that cut both strands of the DNA helix simultaneously in order to manage DNA tangles and supercoils. Both of the copper complexes displayed strong inhibition of human topoisomerase IIα at activities between 2-4 μM for [Cu(PTZ-ETSC)Cl], and between 8-10 μM for the [Cu(PTZ-tBTSC)Cl] complex. It provides a molecular model of the enzyme as an ATP-modulated clamp with two sets of jaws at opposite ends, connected by multiple joints. Topoisomerase II does double strands break. Another duplex, termed the transport segment (T-segment), is captured by the ATP-operated clamp (N-gate) and . topoisomerase I and II inhibitory activity. The structure of DNA-bound human topoisomerase II alpha: conformational mechanisms for coordinating inter-subunit interactions with DNA cleavage. Purification of topoisomerase II from amsacrine-resistant P388 leukemia cells. The structure of DNA-bound human topoisomerase II alpha: conformational mechanisms for coordinating inter-subunit interactions with DNA cleavage. Changing the Linking Number of Circular DNA Topoisomerase I is changing the linking number of circular DNA by . Topoisomerase II DNA-gyrase during takes energy from ATP hydrolysis to introduce tight supercoils into the DNA helix with a view to condense the chromosome (chromosome . Biol. To overcome the limitations of known Top2 inhibitors, novel Top2 catalytic inhibitors with new scaffolds were identified by structure-based virtual screening. But topoisomerase-I passes a single strand and topoisomerase-II passes double-stranded DNA. 49 This pocket is solvent accessible in our TOP2A structure, but insufficiently large to accommodate drug. In the eukaryotic cell, the topological structure of DNA is modulated by two groups of ubiquitous enzymes known as type I and type I1 topo- isomerases. DNA Topoisomerase II Structure Topoisomerase II is a homodimer, which functions by clamping onto DNA, positioning its catalytic residues next to two Mg ions and the DNA backbone. This allows the physical space for another strand of DNA to be synthesized, free from worry of. II. AU - Schmidt, Bryan H. AU - Heslop, Pauline. A second duplex is then passed through the break, and the break is sealed by reversing transesterification ( 9 ). Topoisomerase II is a heterodimer. Eur J Cancer . Mycobacterium tuberculosis (Mtb) infects one-third of the world's population and in 2013 accounted for 1.5 million deaths. Biochemistry 40, 712 (2001). The discovery that certain indenoisoquinolines inhibit the religation reaction of DNA in the topoisomerase I-DNA-indenoisoquinoline ternary complex led to a structure-based drug design research program which resulted in three representatives that entered Phase I clinical trials in cancer patients at the National Cancer Institute. Type I enzymes (topo- isomerase I and the evolutionarily distinct topoisomerase 111) inter- convert different topological forms of DNA by . A protocol comprising several substructural and protein structure-based three-dimensional pharmacophore filters enabled the successful retrieving of inhibitors of the enzyme from large databases of compounds, thus validating the approach. Cell line selectivity and DNA breakage properties of the antitumour agent N-[2-(dimethylamino)ethyl]acridine-4-carboxamide: role of DNA topoisomerase II. Topoisomerase I and II inhibitors: chemical structure, mechanisms of action and role in cancer chemotherapy View the table of contents for this issue, or go to the journal homepage for more Home Search Collections Journals About Contact us My IOPscience. These results are consistent with the findings of Wendorff and colleagues , who noted that the human Top2α structure shows differences to the Top2β-DNA-etoposide structure as well as the majority of topoisomerase II structures solved. Davies G.J. 3. The X-ray structure of a 42 kDa amino-terminal fragment of the GyrB subunit of E. coli DNA topoisomerase II (DNA gyrase) shows that it forms a dimer in the presence of a non- hydrolyzable ATP analog [Wigley D.B. Importantly, we found that TOP2 deficiency in both yeast and . 29. Docking Results 3.1.1. T1 - The structure of DNA-bound human topoisomerase II alpha. antiparallel -sheet in a tertiary structure similar to that of the N domainofvacciniaTopIB(22).Thefirsthelix, 0N,whichhasnoequiv-alent in vaccinia TopIB, packs against the C domain. The topoisomerase II core was later solved in new conformations, including one by Fass et al. We also observed an enrichment of DNA secondary structure-prone sites overlapping transcription start sites (TSSs) and CCCTC-binding factor (CTCF) binding sites, and uncovered an increase in DSBs at highly stable DNA secondary structure regions, in response to etoposide, an inhibitor of topoisomerase II (TOP2) re-ligation activity. Both of the copper complexes displayed strong inhibition of human topoisomerase IIα at activities between 2 - 4 µM for [Cu(PTZETSC)Cl]- , and between 8 - 10 µM for . Services. Synthesis and structure of [(η 6-p-cymene)Ru(2-anthracen-9-ylmethylene-N-ethylhydrazinecarbothioamide)Cl]Cl; biological evaluation, topoisomerase II inhibition and reaction with DNA and human serum albumin† Research . The x-ray crystal structure of the [Cu(PTZ-tBTSC)Cl] complex shows that the complex adopts a square planar arrangement around the copper(II) ion, but forms a sulfur-bridged dimer in the solid state. Interestingly, a magnesium ion is modelled at the level of the Toprim Glu450, Asp527 and Asp 529 residues, essentially confirming the . Topoisomerase II, however, binds mitotic chromatin after depletion of DmSMC4 but it is no longer confined to a central axial structure and becomes diffusely distributed all over the chromatin. The crystal structure of a large fragment of yeast type II DNA topoisomerase reveals a heart-shaped dimeric protein with a large central hole. PubMed. Topoisomerase alpha is showns as a monomer and topoisomerase beta is shown as a dimer. 1). In Figure 1Žc, d., the present results from GNM analysis for the type II structure of a 59 kDa fragment of GyrA is dis- DNA topoisomerases, topoisomerase II Žtopo II., played w 22x , which is sequentially homologous to and gyrase A ŽGyrA.. DNA topoisomerases are the C-terminal of two-thirds of topo II. Molecules of human topoisomerase II visualized by STEM were formed of three domains, a dense globular core domain "90 A in diameter flanked by two smaller domains 50-60 A in diameter (Fig. These enzymes appear to conform to the pattern set by their yeast counterparts both in terms of overall structure and substrate specificity. Watt and Hickson (1994) reviewed in extenso the structure and function of type II DNA topoisomerases. Purpose : Quantitative structure-activity studies were performed on a series of benzoquinone mustard (BM) bifunctional alkylating agents to determine whether DNA topoisomerase II (topo II) inhibition was responsible for cell growth inhibition. 2003; 100:10629-34. This has stimulated a great deal of interest in the design and . The main difference between Topoisomerase I and II is that topoisomerase I cut one strand of the DNA double helix whereas topoisomerase II cut both strands of the DNA double helix.Furthermore, topoisomerase I do not require ATP hydrolysis while topoisomerase II requires ATP hydrolysis. Gentry A. C., et al., Interactions between the etoposide derivative F14512 and human type II topoisomerases . and one by Dong et al. It cuts both strands of one DNA double helix, keeping a firm grip on both halves. Google Scholar. Proc Natl Acad Sci U S A. Class II topoisomerase solves this problem by allowing one DNA helix to pass through the other one. Type II topoisomerases are enzymes that can create a transient break in one DNA duplex via transesterification of the phosphodiester bond, covalently linking the DNA ends to tyrosyl groups in each monomer. In order to perform docking studies, crystal structure of DNA-bound human topoisomerase II alpha (PDB code: 4FM9) was used as template. To date, there is limited structural information on type II enzymes. DNA Breaking Topoisomerase I does single strand breaks. Structure-activity relationship study revealed that indenopyridine compounds with hydroxyl group at 2-phenyl ring in combination with furyl or thienyl moiety at 4-position are important for topoisomerase inhibition. Among all the synthesized compounds, compound 17 emerged as the most promising topoisomerase . What is Topoisomerase II? Especially, compound 10 exhibited the most potent cytotoxicity better than positive controls. Industry. Dong and Berger have described a structure of the breakage reunion domain of yeast topoisomerase II (Top2) bound to DNA 36. 2012, (424):109−24. The general mechanism for the type II topos begins with the binding of one DNA duplex, termed the gate segment (G-segment), at the DNA gate. Energy (in the form of ATP) is required for making conformational changes in these extra domains. Crossref. The experimental analysis of binding site shows that ARG 727, ARG 672, ARG 673, ARG 929, GLY 1007, GLY 852 and GLY 777could be the catalytic site residue present in the structure of human . Dodson E.J. The structure of the C domain, which contains the active site, is similar to the catalytic domain of vaccinia TopIB (7). Changing the Linking Number of Circular DNA Topoisomerase I is changing the linking number of circular DNA by . Structure-activity relationship study indicated that 2,2':6',2 . In particular, compound 8 showed good in vitro antiproliferative activity with a broad spectrum. The study combines ligand- and structure-based drug design methods including pharmacophore models, homology modelling, docking, and virtual screening of the National Cancer Institute compound database. They are broadly classified into two categories namely, Type II A and Type IIB. A recent landmark structure of human TOP2B in complex with etoposide establishes the binding pocket and modality for this class of topoisomerase II poisons. Structure of the topoisomerase II ATPase region and its mechanism of inhibition by the chemotherapeutic agent ICRF-187. The structure of a large fragment of yeast topoisomerase II [20] shows that this protein also has a large hole formed by a protein dimer, with each monomer containing one active site. Topoisomerase II does double strands break. Topoisomerase I and II inhibitory activity, cytotoxicity, and structure-activity relationship study of dihydroxylated 2,6-diphenyl-4-aryl pyridines. Name Topoisomerase II Inhibitors Accession Number DBCAT000549 Description. Included in this category are a variety of ANTINEOPLASTIC AGENTS which target the eukaryotic form of topoisomerase II and ANTIBACTERIAL AGENTS which target the prokaryotic form of topoisomerase II. Wendorff et al. Methods : Topo II inhibition was evaluated by decatenation and agarose gel electrophoresis assays. 1 c-e), consistent with the homodimeric structure of . To investigate the relationship between the molecular structure and biological activity of polypyridyl RuII complexes, such as DNA binding, photocleavage ability, and DNA topoisomerase and RNA polymerase inhibition, six new (Ru(bpy)2(dppz))2+ (bpy=2,2′‐bipyridine; dppz=dipyrido(3,2‐a:2,′,3′‐c)phenazine) analogs have been synthesized and characterized by means of 1H‐NMR . The final model contains residues 7-258, 276-334, and 340-406, and was refined to a working R factor of 20.6% and an R free of 24.1% (Table 1, which is published as supporting information on the PNAS web site, www . The enzyme adopts a domain-swapped configuration wherein the ATPase domain of one protomer sits atop the nucleolytic region of its partner subunit. J. Mol. Substitution of hydroxyl group on the para position showed better cytotoxicity. Schneider E, et al. Structure of ATPase Domain from S. cerevisiae topo II. Compounds that inhibit the activity of DNA TOPOISOMERASE II. Topoisomerase II must need ATP hydrolyzing for its function. Structure Topoisomerase I is a monomer. Type II topoisomerase change the linking number of circular DNA by ± 2. Toxins and Treatments [Google Scholar] Drake FH, Zimmerman JP, McCabe FL, Bartus HF, Per SR, Sullivan DM, Ross WE, Mattern MR, Johnson RK, Crooke ST, et al. Introduction The improvement of the efficacy of the treatment of cancer patients is the biggest social problem in the world in general and . 15. Binding Site analysis. A human topoisomerase II α model provided an insight into the structural features responsible for the activity of the enzyme. From the 8 compounds identified from the computational work, 6 were tested for their capacity to poison topoisomerase II in vitro: 4 showed selective inhibitory activity for the aover the b . The crystal structure of the DNA binding and cleavage core of S. cerevisiae type IIA topoisomerase bound to prospective gate-segment DNA has been recently reported and the structural organization of the catalytic site dissected at atomic resolution . Abstract Human DNA topoisomerase II (Top2) is a promising target for cancer treatment. Thus, monocyclic quinones have potential as anticancer agents, and investigation of the structural origins of their . The crystal structure of a large fragment of yeast type II DNA topoisomerase reveals a heart-shaped dimeric protein with a large central hole. LhhAx, yiFAJF, NDByW, kaCr, BrKRhu, CqhQe, NlA, LqgUf, gAnt, IsFh, XfjFa,

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topoisomerase ii structure

topoisomerase ii structure