Emtricitabine (FTC) and lamivudine (3TC), containing an oxathiolane ring with unnatural (-)-stereochemistry, are widely used nucleoside reverse transcriptase inhibitors (NRTIs) in anti-HIV therapy. Treatment with FTC or 3TC primarily selects for the HIV-1 RT M184V/I resistance mutations. Here we provide a comprehensive kinetic and structural basis for inhibiting HIV-1 RT by (-)-FTC-TP and (-)-3TC-TP and drug resistance by M184V. (-)-FTC-TP and (-)-3TC-TP have higher binding affinities (1/K d) for wild-type RT but slower incorporation rates than dCTP. HIV-1 RT ternary crystal structures with (-)-FTC-TP and (-)-3TC-TP corroborate kinetic results demonstrating that their oxathiolane sulfur orients toward the DNA primer 3'-terminus and their triphosphate exists in two different binding conformations. M184V RT displays greater (>200-fold) K d for the L-nucleotides and moderately higher (>9-fold) K d for the D-isomers compared to dCTP. The M184V RT structure illustrates how the mutation repositions the oxathiolane of (-)-FTC-TP and shifts its triphosphate into a non-productive conformation.

中文翻译：

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阐明 L-核苷酸与 HIV-1 逆转录酶的分子相互作用以及 M184V 引起耐药性的机制。

恩曲他滨 (FTC) 和拉米夫定 (3TC) 含有具有非天然 (-)-立体化学的氧硫杂环戊烷环，是广泛用于抗 HIV 治疗的核苷逆转录酶抑制剂 (NRTI)。FTC 或 3TC 治疗主要选择 HIV-1 RT M184V/I 耐药突变。在这里，我们提供了通过 (-)-FTC-TP 和 (-)-3TC-TP 抑制 HIV-1 RT 以及通过 M184V 抑制耐药性的全面动力学和结构基础。(-)-FTC-TP 和 (-)-3TC-TP 对野生型 RT 具有更高的结合亲和力 (1/K d)，但掺入率比 dCTP 慢。HIV-1 RT 具有 (-)-FTC-TP 和 (-)-3TC-TP 的三元晶体结构证实了动力学结果，表明它们的氧硫杂环戊烷硫朝向 DNA 引物 3' 末端，并且它们的三磷酸盐以两种不同的结合构象存在。与 dCTP 相比，M184V RT 对 L-核苷酸表现出更大（>200 倍）的 Kd，对 D-异构体表现出稍高（>9 倍）的 Kd。M184V RT 结构说明了突变如何重新定位 (-)-FTC-TP 的氧硫戊环并将其三磷酸转变为非生产性构象。