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  • Oxford University Press  (11)
  • International Union of Crystallography (IUC)  (7)
  • 2010-2014  (18)
  • 1965-1969
  • 1
    Publication Date: 2013-12-07
    Description: Type II topoisomerases (Top2s) alter DNA topology via the formation of an enzyme–DNA adduct termed cleavage complex, which harbors a transient double-strand break in one DNA to allow the passage of another. Agents targeting human Top2s are clinically active anticancer drugs whose trapping of Top2-mediated DNA breakage effectively induces genome fragmentation and cell death. To understand the structural basis of this drug action, we previously determined the structure of human Top2 β-isoform forming a cleavage complex with the drug etoposide and DNA, and described the insertion of drug into DNA cleavage site and drug-induced decoupling of catalytic groups. By developing a post-crystallization drug replacement procedure that simplifies structural characterization of drug-stabilized cleavage complexes, we have extended the analysis toward other structurally distinct drugs, m -AMSA and mitoxantrone. Besides the expected drug intercalation, a switch in ribose puckering in the 3'-nucleotide of the cleavage site was robustly observed in the new structures, representing a new mechanism for trapping the Top2 cleavage complex. Analysis of drug-binding modes and the conformational landscapes of the drug-binding pockets provide rationalization of the drugs’ structural-activity relationships and explain why Top2 mutants exhibit differential effects toward each drug. Drug design guidelines were proposed to facilitate the development of isoform-specific Top2-targeting anticancer agents.
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
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  • 2
    Publication Date: 2013-06-23
    Description: With the rapid accumulation of our knowledge on diseases, disease-related genes and drug targets, network-based analysis plays an increasingly important role in systems biology, systems pharmacology and translational science. The new release of VisANT aims to provide new functions to facilitate the convenient network analysis of diseases, therapies, genes and drugs. With improved understanding of the mechanisms of complex diseases and drug actions through network analysis, novel drug methods (e.g., drug repositioning, multi-target drug and combination therapy) can be designed. More specifically, the new update includes (i) integrated search and navigation of disease and drug hierarchies; (ii) integrated disease–gene, therapy–drug and drug–target association to aid the network construction and filtering; (iii) annotation of genes/drugs using disease/therapy information; (iv) prediction of associated diseases/therapies for a given set of genes/drugs using enrichment analysis; (v) network transformation to support construction of versatile network of drugs, genes, diseases and therapies; (vi) enhanced user interface using docking windows to allow easy customization of node and edge properties with build-in legend node to distinguish different node type. VisANT is freely available at: http://visant.bu.edu .
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
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  • 3
    Publication Date: 2014-04-03
    Description: Klebsiella pneumoniae PmrA is a polymyxin-resistance-associated response regulator. The C-terminal effector/DNA-binding domain of PmrA (PmrA C ) recognizes tandem imperfect repeat sequences on the promoters of genes to induce antimicrobial peptide resistance after phosphorylation and dimerization of its N-terminal receiver domain (PmrA N ). However, structural information concerning how phosphorylation of the response regulator enhances DNA recognition remains elusive. To gain insights, we determined the nuclear magnetic resonance solution structure of PmrA C and characterized the interactions between PmrA C or BeF 3 – -activated full-length PmrA (PmrA F ) and two DNA sequences from the pbgP promoter of K. pneumoniae . We showed that PmrA C binds to the PmrA box, which was verified to contain two half-sites, 5'-CTTAAT-3' and 5'-CCTAAG-3', in a head-to-tail fashion with much stronger affinity to the first than the second site without cooperativity. The structural basis for the PmrA C –DNA complex was investigated using HADDOCK docking and confirmed by paramagnetic relaxation enhancement. Unlike PmrA C , PmrA F recognizes the two sites simultaneously and specifically. In the PmrA F –DNA complex, PmrA N may maintain an activated homodimeric conformation analogous to that in the free form and the interactions between two PmrA C molecules aid in bending and binding of the DNA duplex for transcription activation.
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
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  • 4
    Publication Date: 2013-09-06
    Description: The X-ray emission from Swift J1644+57 is not steadily decreasing; instead, it shows multiple pulses with declining amplitudes. We model the pulses as reverse shocks from collisions between the late ejected shells and the externally shocked material, which is decelerated while sweeping the ambient medium. The peak of each pulse is taken as the maximum emission of each reverse shock. With a proper set of parameters, the envelope of peaks in the light curve as well as the spectrum can be modelled well.
    Print ISSN: 0035-8711
    Electronic ISSN: 1365-2966
    Topics: Physics
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  • 5
    Publication Date: 2012-03-15
    Description: The asymmetric unit of the title compound, [MnCl2(C16H20N2O)4]·2C16H20N2O, is composed of two coordinating N-(adamantan-1-yl)pyridine-4-carboxamide molecules, one Cl− anion, an MnII ion, lying on an inversion centre, and one free N-(adamantan-1-yl)pyridine-4-carboxamide molecule. The distorted octahedral Mn environment comprises two terminal Cl atoms and four monodentate N atoms from four organic ligands. All the carbamoyl N atoms are involved in intermolecular N—H...O hydrogen-bonding interactions which link the molecules into a chain along the a axis.
    Electronic ISSN: 1600-5368
    Topics: Chemistry and Pharmacology , Geosciences
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  • 6
    Publication Date: 2012-08-21
    Description: Disruptions of normal apoptotic pathways, which are mainly mediated by caspases, play an essential role in cancer development. Caspase-8 (CASP8) is encoded by the CASP8 gene and is centrally involved in the apoptosis of T lymphocytes. The association between a six-nucleotide deletion polymorphism (-652 6N del) of the CASP8 gene and the risk of cancer is widely reported; however, study results have been inconsistent and contradictory. To evaluate the association between the CASP8 -652 6N del polymorphism and the risk of cancer and to overcome the limitations of any individual study, a meta-analysis based on a total of 23 700 cases and 26 412 controls from 30 case–control studies was conducted. The results of the overall analysis suggested that the CASP8 -652 6N del polymorphism is associated with decreased risk of cancer for the allele contrast [del versus ins: odd ratio (OR) = 0.86, 95% confidence interval (CI) = 0.80–0.92], the additive genetic model (del/del versus ins/ins: OR = 0.78, 95% CI = 0.69–0.88), the dominant genetic model (del/del+del/ins versus ins/ins: OR = 0.83, 95% CI = 0.78–0.89) and the recessive genetic model (del/del versus ins/ins+del/ins: OR = 0.84, 95% CI = 0.75–0.93). In addition, after stratification for ethnicity and cancer type, significantly reduced risk was found for Asians and Caucasians as well as for individuals in the colorectal cancer group and the ‘other cancers’ group. Accordingly, there is an association between the CASP8 -652 6N del polymorphism and reduced cancer risk, especially among Asians, Caucasians and those with colorectal cancer. However, further research, such as studies focusing on additional ethnic groups and cancer types, is needed to provide a more exact and comprehensive synthesis conclusion.
    Print ISSN: 0267-8357
    Electronic ISSN: 1464-3804
    Topics: Biology , Medicine
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  • 7
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    International Union of Crystallography (IUC)
    Publication Date: 2012-06-03
    Description: During the formation of the title salt, C7H10N+·C3H3O4−, an H atom of a carboxyl group was transferred to the amino group. All non-H atoms of the cation are essentially coplanar [r.m.s. deviation = 0.007 (4) Å]. The mean planes of the carboxylate and carboxyl groups of the anion form a dihedral of 69.67 (1)°. In the crystal, N—H...O and O—H...O hydrogen bonds connect the anions and cations, forming a two-dimensional network parallel to the bc plane.
    Electronic ISSN: 1600-5368
    Topics: Chemistry and Pharmacology , Geosciences
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  • 8
    Publication Date: 2012-05-13
    Description: The asymmetric unit of the title compound, C6H5N2+·H2PO4−·C6H4N2·H3PO4, contains one 4-cyanopyridinium cation, one H2PO4− anion, one independent isonicotinonitrile molecule and one independent H3PO4 molecule. The dihedral angle between the mean planes of the separate protonated and unprotonated pyridine rings is 9.93 (8)°. In the crystal, N—H...O and O—H...N hydrogen bonds and weak C—H...O and C—H...N intermolecular interactions connect the organic molecules into a two-dimensional network parallel to the ac plane. O—H...O hydrogen-bonding interactions involving the H2PO4− anions and H3PO4 molecules provide additional support from the inorganic groups Weak π–π stacking interactions between the pyridine rings of neighbouring organic molecules [centroid–centroid distances = 3.711 (4) and 3.784 (2) Å] further link the layers into a three-dimensional network.
    Electronic ISSN: 1600-5368
    Topics: Chemistry and Pharmacology , Geosciences
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  • 9
    Publication Date: 2012-01-15
    Description: In the centrosymmetric dimeric title compound, [Cu2Cl4(C16H20N2O)4]·0.5H2O, the CuII atom is in a distorted trigonal–bipyramidal environment defined by two bridging Cl atoms, one terminal Cl atom and two N atoms from two monodentate 4-(adamantan-1-ylcarbamoyl)pyridine ligands. The amine N atoms are involved in intramolecular N—H...O and intermolecular N—H...Cl hydrogen bonds. The latter hydrogen bonds link the complex molecules into a ribbon along [010]. The uncoordinated water molecule is 0.25-occupied.
    Electronic ISSN: 1600-5368
    Topics: Chemistry and Pharmacology , Geosciences
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  • 10
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    International Union of Crystallography (IUC)
    Publication Date: 2012-01-22
    Description: The asymmetric unit of the title complex, [Fe(C5H5)(C11H17N)]ClO4, contains two independent allyl(ferrocenylmethyl)dimethylammonium cations and two ClO4− anions. The anions are disordered each over two sets of sites, with an occupancy ratio of 0.617 (6):0.383 (6). The distances from the Fe atoms to the centroids of the unsubstituted and substituted cyclopentadienyl (Cp) rings are 1.645 (1)/1.657 (1) and 1.644 (1)/1.647 (1) Å. The dihedral angles between the two Cp rings are 2.49 (3) and 1.45 (4)° in the two ferrocenyl groups of the cations.
    Electronic ISSN: 1600-5368
    Topics: Chemistry and Pharmacology , Geosciences
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