9 research outputs found
[Synthesis, Structure and Some Biochemical-properties of 3'-branched Thymidines and Their 5'-phosphate Derivatives]
A full scheme of synthesizing 3'-C-methyl-2'-deoxynucleosides and 3'-C-methylidene-28,3'-dideoxythymidine has been developed by using 2-deoxyribose. The stereoselectivity of the Grignard reagent's attachment to 2-deoxyfuranose 3-ulosides determined by the substitute configuration at Cl and the condensation stereoselectivity of 3-C-methyl-2-deoxyfuranosides with silylated thymine dependent on the configuration of the hydroxyl or-OBz group at C3 have been studied. The structure of the resultant compounds has been evidenced by H-1 and C-13 NMR, UV spectroscopies and C, H, and N analysis. The C2'-endo-C1-exo-conformation, the anti-conformation of the thymine base in relation to the glycoside bond and the gosh+-conformation in relation to the C4'-C5' bond are characteristic of the structure of 3'-C-methyl-2'-deoxythymidine in the crystal. 3'-C-Metyl-2'-deoxythymidine-5'-triphosphate exhibited the properties of the competitive inhibitor against 2'-deoxythimidine 5'-triphosphate in the synthesis of DNA catalyzed by various DNA-polymerases and reverse transcriptases. But none of these enzymes incorporated this compound into the growing DNA chain. At the same time 3'-C-methylidene-2',3'-dideoxythymidine-5'-triphosphate was incorporated into the 3'-end of the chain of DNA catalyzed by HIV reverse transcriptase, though the latter having a low efficacy. 3'-C-Methyl-2'-deoxythymidine failed to suppress HIV-1 production in the cultured MT-4 cells, its 5'-phosphite exhibiting a low activity under the same conditions
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The p53 tetramer shows an induced-fit interaction of the C-terminal domain with the DNA-binding domain
The Trp53 gene is the most frequently mutated gene in all human cancers. Its protein product p53 is a very powerful transcription factor that can activate different biochemical pathways and affect the regulation of metabolism, senescence, DNA damage response, cell cycle and cell death. The understanding of its function at the molecular level could be of pivotal relevance for therapy. Investigation of long-range intra- and interdomain communications in the p53 tetramer-DNA complex was performed by means of an atomistic model that included the tetramerization helices in the C-terminal domain, the DNA-binding domains and a consensus DNA-binding site of 18 base pairs. Nonsymmetric dynamics are illustrated in the four DNA-binding domains, with loop L1 switching from inward to outward conformations with respect to the DNA major groove. Direct intra- and intermonomeric long-range communications between the tetramerization and DNA-binding domains are noted. These long-distance conformational changes link the C terminus with the DNA-binding domain and provide a biophysical rationale for the reported functional regulation of the p53 C-terminal region. A fine characterization of the DNA deformation caused by p53 binding is obtained, with 'static' deformations always present and measured by the slide parameter in the central thymine-adenine base pairs; we also detect 'dynamic' deformations switched on and off by particular p53 tetrameric conformations and measured by the roll and twist parameters in the same base pairs. These different conformations can indeed modulate the electrostatic potential isosurfaces of the whole p53-DNA complex. These results provide a molecular/biophysical understanding of the evident role of the C terminus in post-translational modification that regulates the transcriptional function of p53. Furthermore, the unstructured C terminus is able to facilitate contacts between the core DNA-binding domains of the tetramer