Crystal structure of tert-butyldimethylsilyl-spiroaminooxathioledioxide-thymine (TSAO-T) in complex with HIV-1 reverse transcriptase (RT) redefines the elastic limits of the non-nucleoside inhibitor-binding pocket.
Crystal structure of tert-butyldimethylsilyl-spiroaminooxathioledioxide-thymine (TSAO-T) in complex with HIV-1 reverse transcriptase (RT) redefines the elastic limits of the non-nucleoside inhibitor-binding pocket.
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DOI：
10.1021/jm101536x
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发表时间：
2011-04-28
影响因子：
7.3
通讯作者：
Arnold E
中科院分区：
文献类型：
--
作者：
Das K;Bauman JD;Rim AS;Dharia C;Clark AD Jr;Camarasa MJ;Balzarini J;Arnold E
叔丁基二甲基甲硅烷基-螺氨基氧硫醚二氧化物（TSAO）化合物具有嵌入的胸苷类似物骨架;然而，TSAO化合物引起非核苷RT抑制剂（NNRTI）抗性突变。RT：7（TSAO-T）复合物的晶体结构显示，7结合在NNRTI结合口袋内，呈“龙”形，并与几乎所有口袋残基广泛相互作用。该结构还解释了TSAO化合物的结构-活性关系和抗性数据。7的结合导致口袋的过度扩张和RT亚结构域的显著重排。这种非最佳的复合物形成显然是（1）RT（p66/p51）二聚体稳定性较低和（2）尽管与RT有广泛的相互作用，但7的效力较低的原因。然而，HIV-1 RT：7结构揭示了新的设计特征，如（1）与YMDD基序的保守Tyr 183相互作用和（2）NNRTI到达聚合酶活性位点的可能途径，该位点可用于设计新的NNRTI。
Tert-butyldimethylsilyl-spiroaminooxathioledioxide (TSAO) compounds have an embedded thymidine-analog backbone; however, TSAO compounds invoke non-nucleoside RT inhibitor (NNRTI) resistance mutations. Our crystal structure of RT:7 (TSAO-T) complex shows that 7 binds inside the NNRTI-binding pocket assuming a “dragon” shape, and interacts extensively with almost all the pocket residues. The structure also explains the structure-activity relationships and resistance data for TSAO compounds. The binding of 7 causes hyper-expansion of the pocket and significant rearrangement of RT subdomains. This non-optimal complex formation is apparently responsible (1) for the lower stability of a RT (p66/p51) dimer and (2) for the lower potency of 7 despite of its extensive interactions with RT. However, the HIV-1 RT:7 structure reveals novel design features, such as (1) interactions with the conserved Tyr183 from the YMDD-motif and (2) a possible way for an NNRTI to reach the polymerase active site that may be exploited in designing new NNRTIs.
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DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
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影响因子：
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10.1038/nsb0595-407
发表时间：
1995-05-01
期刊：
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影响因子：
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作者：
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通讯作者：
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DOI：
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发表时间：
2010-02
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
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作者：
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Zwart PH