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  • DYANA  (1)
  • Keywords Antiangiogenesis  (1)
  • NMR structure  (1)
  • ras mutation  (1)
  • ribonuclease H  (1)
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  • 1
    ISSN: 0948-5023
    Schlagwort(e): Keywords Antiangiogenesis ; Antiproliferation ; Docking study ; Drug design ; ras mutation
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: Abstract Farnesyltransferase (FT) inhibitors can repress tumor cell proliferation without substantially interfering with normal cell growth and are thus promising in cancer treatment. A detailed knowledge of how substrates and inhibitors bind to FT at the atomic level can expedite screening and rational design of improved FT inhibitors. Here we report theoretical models of the FT complexed with FPP and the potent nonpeptidic inhibitor SCH 56580 and other inhibitor-FPP-FT ternary complexes derived from the docking studies prior to any crystal structures of the FT liganded with nonpeptidic inhibitors. On the basis of these models we evaluate the roles of FPP, Zn2+ and the zinc-coordinated water molecule in inhibitor binding, and propose the structural determinants of binding of nonpeptidic FT inhibitors. Furthermore, we suggest the use of the FPP-FT binary complex as a novel and effective drug target structure for screening and rational design of improved FT inhibitors.
    Materialart: Digitale Medien
    Standort Signatur Erwartet Verfügbarkeit
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  • 2
    ISSN: 1573-5001
    Schlagwort(e): AIDS ; DYANA ; HIV-1 ; NMR structure ; ribonuclease H ; RNA-DNA hybrid ; torsion angle dynamics
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Biologie , Chemie und Pharmazie
    Notizen: Abstract A high-quality NMR solution structure of the chimeric hybrid duplex r(gcaguggc)⋅r(gcca)d(CTGC) was determined using the program DYANA with its recently implemented new module FOUND, which performs exhaustive conformational grid searches for dinucleotides. To ensure conservative data interpretation, the use of 1H-1H lower distance limit constraints was avoided. The duplex comprises the tRNA–DNA junction formed during the initiation of HIV-1 reverse transcription. It forms an A-type double helix that exhibits distinct structural deviations from a standard A-conformation. In particular, the minor groove is remarkably narrow, and its width decreases from about 7.5 Å in the RNA/RNA stem to about 4.5 Å in the RNA/DNA segment. This is unexpected, since minor groove widths for A-RNA and RNA/DNA hybrid duplexes of ∼11 Å and ∼8.5 Å, respectively, were previously reported. The present, new structure supports that reverse transcriptase-associated RNaseH specificity is related primarily to conformational adaptability of the nucleic acid in 'induced-fit'-type interactions, rather than the minor groove width of a predominantly static nucleic acid duplex.
    Materialart: Digitale Medien
    Standort Signatur Erwartet Verfügbarkeit
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