Active-site deformation in the structure of HIV-1 RT with HBV-associated septuple amino acid substitutions rationalizes the differential susceptibility of HIV-1 and HBV against 4'-modified nucleoside RT inhibitors.
Active-site deformation in the structure of HIV-1 RT with HBV-associated septuple amino acid substitutions rationalizes the differential susceptibility of HIV-1 and HBV against 4'-modified nucleoside RT inhibitors.
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HIV-1 RT 结构中的活性位点变形与 HBV 相关的七氨基酸取代合理化了 HIV-1 和 HBV 对 4 修饰核苷 RT 抑制剂的不同敏感性。
DOI：
10.1016/j.bbrc.2019.01.026
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发表时间：
2019
影响因子：
3.1
通讯作者：
Mitsuya,Hiroaki
中科院分区：
文献类型：
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作者：
Yasutake,Yoshiaki;Hattori,Shin-Ichiro;Tamura,Noriko;Matsuda,Kouki;Kohgo,Satoru;Maeda,Kenji;Mitsuya,Hiroaki
核苷类似物逆转录酶（RT）抑制剂（NRTI）是抗B型肝炎病毒（HBV）和人类免疫缺陷病毒1型（HIV-1）的主要抗病毒药物。然而，HBV RT臭名昭著的不溶性阻碍了原子解析结构研究和合理的抗HBV药物设计。在这里，我们创建了HIV-1 RT突变体含有HBV模拟六或七个氨基酸取代的核苷结合位点（N-位点），并验证这些突变体保留RT活性。最活跃的RT突变体，HIV-1 RT 7 MC，携带Q151 M/G112 S/D113 A/Y115 F/F116 Y/F160 L/I159 L被成功结晶，并确定其三维结构与DNA的复合物：dGTP/恩替卡韦-三磷酸（ETV-TP），一种有效的抗HBV鸟苷类似物RT抑制剂，分辨率分别为2.43 μ m和2.60 μ m。这些结构揭示了N-位点氨基酸侧链的显著位置重排，阐明了HIV-1和HBV对最近报道的4种β-修饰的NRTI的差异敏感性的机制。
Nucleoside analogue reverse transcriptase (RT) inhibitors (NRTIs) are major antiviral agents against hepatitis B virus (HBV) and human immunodeficiency virus type-1 (HIV-1). However, the notorious insoluble property of HBV RT has prevented atomic-resolution structural studies and rational anti-HBV drug design. Here, we created HIV-1 RT mutants containing HBV-mimicking sextuple or septuple amino acid substitutions at the nucleoside-binding site (N-site) and verified that these mutants retained the RT activity. The most active RT mutant, HIV-1 RT7MC, carrying Q151M/G112S/D113A/Y115F/F116Y/F160L/I159L was successfully crystallized, and its three-dimensional structure was determined in complex with DNA:dGTP/entecavir-triphosphate (ETV-TP), a potent anti-HBV guanosine analogue RT inhibitor, at a resolution of 2.43 Å and 2.60 Å, respectively. The structures reveal significant positional rearrangements of the amino acid side-chains at the N-site, elucidating the mechanism underlying the differential susceptibility of HIV-1 and HBV against recently reported 4ʹ-modified NRTIs.
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影响因子：
7.6
作者：
Clark DN;Hu J
通讯作者：
Hu J
一致。
DOI：
10.1097/iae.0000000000001602
发表时间：
2017
期刊：
Retina (Philadelphia, Pa.)
影响因子：
--
作者：
Todorich,Bozho;Thanos,Aristomenis;Yonekawa,Yoshihiro;Thomas,BenjaminJ;Faia,LisaJ;Chang,Emmanuel;Shulman,Julia;Olsen,KarlR;Blair,MichaelP;Shapiro,MichaelP;Ferrone,Philip;Vajzovic,Lejla;Toth,CynthiaA;Lee,ThomasC;Robinson,
通讯作者：
Robinson,
影响因子：
5.4
作者：
Voeroes, Judit;Urbanek, Annika;Ferguson, Neil
通讯作者：
Ferguson, Neil
影响因子：
5.6
作者：
Lansdon, Eric B.;Samuel, Dharmaraj;Swaminathan, S.
通讯作者：
Swaminathan, S.
影响因子：
16.8
作者：
通讯作者：
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