HIV-1 with HBV-associated Q151M substitution in RT becomes highly susceptible to entecavir: structural insights into HBV-RT inhibition by entecavir.
HIV-1 with HBV-associated Q151M substitution in RT becomes highly susceptible to entecavir: structural insights into HBV-RT inhibition by entecavir.
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与HBV相关的Q151M在RT中取代的HIV-1非常容易受到Entecavir的影响：对Entecavir抑制HBV-RT抑制的结构见解。
DOI：
10.1038/s41598-018-19602-9
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发表时间：
2018-01-26
影响因子：
4.6
通讯作者：
Mitsuya H
中科院分区：
文献类型：
--
作者：
Yasutake Y;Hattori SI;Hayashi H;Matsuda K;Tamura N;Kohgo S;Maeda K;Mitsuya H
B型肝炎病毒（HBV）逆转录酶（RT）是病毒复制所必需的，也是重要的药物靶点。尽管如此，HBV RT臭名昭著的不溶性阻碍了实验结构研究和基于结构的药物设计。在这里，我们证明了一个Q151 M取代单独在人类免疫缺陷病毒1型（HIV-1）RT的核苷酸结合位点（N-位点），使HIV-1对恩替卡韦（ETV），一种有效的核苷类似物RT抑制剂（NRTI）对HBV高度敏感。结果表明，Met 151与ETV的环戊基亚甲基形成瞬时疏水相互作用，ETV的特征疏水部分。因此，我们解决了HIV-1 RTQ 151 M：DNA复合物与结合的dGTP或ETV-三磷酸（ETV-TP）的晶体结构。结构分析表明，ETV-TP的N位与dGTP和NRTI/dNTP的结合位置相比，与3′-端核苷酸的核糖环稍有距离。此外，结合ETV-TP的突出亚甲基直接向后推动Met 184的侧链。Met 184是在用较小的Ile/瓦尔取代后赋予ETV抗性的关键残基。这些结果为NRTI与N位点的结合提供了新的见解，并进一步为开发新型抗HBV/HIV-1 RT抑制剂以克服关键耐药性提供了重要线索。
Hepatitis B virus (HBV) reverse transcriptase (RT) is essential for viral replication and is an important drug target. Nonetheless, the notorious insolubility of HBV RT has hindered experimental structural studies and structure-based drug design. Here, we demonstrate that a Q151M substitution alone at the nucleotide-binding site (N-site) of human immunodeficiency virus type-1 (HIV-1) RT renders HIV-1 highly sensitive to entecavir (ETV), a potent nucleoside analogue RT inhibitor (NRTI) against HBV. The results suggest that Met151 forms a transient hydrophobic interaction with the cyclopentyl methylene of ETV, a characteristic hydrophobic moiety of ETV. We thus solved the crystal structures of HIV-1 RTQ151M:DNA complex with bound dGTP or ETV-triphosphate (ETV-TP). The structures revealed that ETV-TP is accommodated at the N-site slightly apart from the ribose ring of the 3′-end nucleotide, compared to the position of bound dGTP and previously reported NRTI/dNTP. In addition, the protruding methylene group of bound ETV-TP directly pushes the side-chain of Met184 backward. Met184 is a key residue that confers ETV resistance upon substitution with smaller Ile/Val. These results provide novel insights into NRTI binding to the N-site and further provide important clues for the development of novel anti-HBV/HIV-1 RT inhibitors to overcome critical drug resistance.
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影响因子：
14.9
作者：
HEMSLEY, A;ARNHEIM, N;GALAS, DJ
通讯作者：
GALAS, DJ
影响因子：
4.8
作者：
Maeda, K;Yoshimura, K;Mitsuya, H
通讯作者：
Mitsuya, H
影响因子：
4.9
作者：
Margot, Nicolas A.;Johnson, Audun;Callebaut, Christian
通讯作者：
Callebaut, Christian
影响因子：
6.4
作者：
Maeda, Y;Venzon, DJ;Mitsuya, H
通讯作者：
Mitsuya, H
DOI：
10.1016/j.biocel.2012.04.006
发表时间：
2012-07
期刊：
The international journal of biochemistry & cell biology
影响因子：
--
作者：
Michailidis E;Kirby KA;Hachiya A;Yoo W;Hong SP;Kim SO;Folk WR;Sarafianos SG
通讯作者：
Sarafianos SG