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首页> 外文期刊>Nucleic Acids Research >Structural and kinetic insights into binding and incorporation of L-nucleotide analogs by a Y-family DNA polymerase
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Structural and kinetic insights into binding and incorporation of L-nucleotide analogs by a Y-family DNA polymerase

机译：Y家族DNA聚合酶结合和掺入L-核苷酸类似物的结构和动力学见解

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摘要

Considering that all natural nucleotides (D-dNTPs) and the building blocks (D-dNMPs) of DNA chains possess D-stereochemistry, DNA polymerases and reverse transcriptases (RTs) likely possess strong D-stereoselectivity by preferably binding and incorporating D-dNTPs over unnatural L-dNTPs during DNA synthesis. Surprisingly, a structural basis for the discrimination against L-dNTPs by DNA polymerases or RTs has not been established although L-deoxycytidine analogs (lamivudine and emtricitabine) and L-thymidine (telbivudine) have been widely used as antiviral drugs for years. Here we report seven high-resolution ternary crystal structures of a prototype Y-family DNA polymerase, DNA, and D-dCTP, D-dCDP, L-dCDP, or the diphosphates and triphosphates of lamivudine and emtricitabine. These structures reveal that relative to D-dCTP, each of these L-nucleotides has its sugar ring rotated by 180. with an unusual O4'-endo sugar puckering and exhibits multiple triphosphate-binding conformations within the active site of the polymerase. Such rare binding modes significantly decrease the incorporation rates and efficiencies of these L-nucleotides catalyzed by the polymerase.
机译：考虑到所有天然核苷酸（D-dNTPs）和DNA链的构建基（D-dNMPs）都具有D-立体化学，DNA聚合酶和逆转录酶（RTs）可能具有较强的D-立体选择性，方法是将D-dNTPs与DNA合成过程中的非天然L-dNTP。令人惊讶的是，尽管L-脱氧胞苷类似物（拉米夫定和恩曲他滨）和L-胸苷（替比夫定）已被广泛用作抗病毒药物多年，但尚未建立通过DNA聚合酶或RT区分L-dNTPs的结构基础。在这里，我们报告原型Y系列DNA聚合酶，DNA和D-dCTP，D-dCDP，L-dCDP或拉米夫定和恩曲他滨的二磷酸盐和三磷酸盐的七个高分辨率三元晶体结构。这些结构表明，相对于D-dCTP，这些L-核苷酸的每个糖环的糖环旋转180°，并具有异常的O4'-内糖褶皱，并在聚合酶的活性位点内表现出多个三磷酸结合构象。这种罕见的结合模式显着降低了聚合酶催化的这些L-核苷酸的掺入率和效率。

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