共查询到20条相似文献,搜索用时 15 毫秒
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Structures of HIV-1 RT-DNA complexes before and after incorporation of the anti-AIDS drug tenofovir 总被引:3,自引:0,他引:3
Tuske S Sarafianos SG Clark AD Ding J Naeger LK White KL Miller MD Gibbs CS Boyer PL Clark P Wang G Gaffney BL Jones RA Jerina DM Hughes SH Arnold E 《Nature structural & molecular biology》2004,11(5):469-474
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Molecular electrostatic potential(MEP) maps of azido thymidine (AZT), some of its analogs and derivatives and certain other 2′,3′-dideoxy nucleosides having different anti-HIV activities have been studied. The optimised hybridization displacement charges (HDC) combined with MNDO Löwdin charges, continuosly distributed in three dimension spherically symmetrically as a Slater cloud at each site were used to compute the MEP maps. The negative MEP region near the O5′ sites of these molecules appears to be of primary importance from the point of view of their anti-HIV activity. The roles of the azido group in AZT and fluorine atoms substituted at different positions in the sugar moiety have been evaluated. The azido group in AZT behaves as a strongly electronegative group. 相似文献
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Matamoros T Franco S Vázquez-Alvarez BM Mas A Martínez MA Menéndez-Arias L 《The Journal of biological chemistry》2004,279(23):24569-24577
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Selmi B Deval J Alvarez K Boretto J Sarfati S Guerreiro C Canard B 《The Journal of biological chemistry》2003,278(42):40464-40472
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The first step for the intracellular retention of several anticancer or antiviral nucleoside analogues is the addition of a phosphate group catalysed by a deoxyribonucleoside kinase such as thymidine kinase 1 (TK1). Recently, human TK1 (HuTK1) has been crystallized and characterized using different ligands. To improve our understanding of TK1 substrate specificity, we performed a detailed, mutation-based comparative structure-function study of the active sites of two thymidine kinases: HuTK1 and Caenorhabditis elegans TK1 (CeTK1). Specifically, mutations were introduced into the hydrophobic pocket surrounding the substrate base. In CeTK1, some of these mutations led to increased activity with deoxycytidine and deoxyguanosine, two unusual substrates for TK1-like kinases. In HuTK1, mutation of T163 to S resulted in a kinase with a 140-fold lower K(m) for the antiviral nucleoside analogue 3'-azido-3'-deoxythymidine (AZT) compared with the natural substrate thymidine. The crystal structure of the T163S-mutated HuTK1 reveals a less ordered conformation of the ligand thymidine triphosphate compared with the wild-type structure but the cause of the changed specificity towards AZT is not obvious. Based on its highly increased AZT activity relative to thymidine activity this TK1 mutant could be suitable for suicide gene therapy. 相似文献
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Selection of mutations in the connection and RNase H domains of human immunodeficiency virus type 1 reverse transcriptase that increase resistance to 3'-azido-3'-dideoxythymidine 总被引:1,自引:0,他引:1
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Brehm JH Koontz D Meteer JD Pathak V Sluis-Cremer N Mellors JW 《Journal of virology》2007,81(15):7852-7859
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3'-Azido-3'-deoxythymidine (AZT) is HIV-inhibitory in human macrophages, which is surprising in view of the low AZT phosphorylation reported in macrophage extracts. To elucidate the mechanism of AZT activation, we studied AZT anabolism as well as catabolism in human lymphocytes and macrophages, and compared it to that of thymidine. Thymidine kinase (TK)-specific activity in mitogen-stimulated lymphocytes was 15 times higher than in macrophages. However, the TK activity per cell was only 1.3 times higher, because of the large macrophage cell volume. Total cellular TK activity, but not specific activity, matched the level of intracellular AZT anabolism. The substrate specificity of TK in macrophages strongly suggests that mitochondrial TK2 was the enzyme phosphorylating thymidine and AZT in these cells, whereas it was cytosolic TK1 in stimulated lymphocytes. In vivo thymidine catabolism was extensive, forming thymine and dihydrothymine. In macrophages more than 95% of the added thymidine (0.5 microM) was degraded within 60 min. AZT, in contrast, was not catabolized, which explains the high AZT nucleotide accumulation, a process opposed only by AZTMP excretion. The lack of catabolism together with phosphorylation by TK2 clarifies how AZT can inhibit human immunodeficiency virus in macrophages. The fact that TK2 and not TK1 phosphorylates AZT in macrophages should have important implications for combination chemotherapy. 相似文献
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Najmudin S Coté ML Sun D Yohannan S Montano SP Gu J Georgiadis MM 《Journal of molecular biology》2000,296(2):613-632