Retroviral Integrase Structure and DNA Recombination Mechanism
Retroviral Integrase Structure and DNA Recombination Mechanism
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DOI：
10.1128/microbiolspec.mdna3-0024-2014
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发表时间：
2014-12-01
影响因子：
3.7
通讯作者：
Cherepanov, Peter
中科院分区：
文献类型：
--
作者：
Engelman, Alan;Cherepanov, Peter
由于人类免疫缺陷病毒1型（HIV-1）整合酶作为药物靶点的重要性，在过去三十年中，逆转录病毒DNA整合的生物化学和结构方面一直是深入研究的焦点。逆转录病毒整合酶作用于逆转录的线性双链病毒DNA产物。整合酶在3'加工反应中切割病毒DNA末端附近的特定磷酸二酯键。然后酶利用链转移过程中产生的病毒DNA 3'-OH基团切割染色体目标DNA，同时将病毒DNA两端连接到目标DNA 5'-磷酸。这两种反应都是通过攻击亲核试剂（用于3‘加工的水分子和用于链转移的病毒DNA 3’-OH）对可剪切的磷酸二酯键进行直接酯交换而进行的。泡沫病毒整合酶- dna复合物原型的x射线晶体结构揭示了整合过程中依次形成的关键核蛋白复合物的结构，并解释了活性位点金属离子在催化中的作用。x射线晶体学进一步阐明了目前用于治疗艾滋病患者的HIV-1整合酶链转移抑制剂的作用机制，并为病毒耐药机制提供了有价值的见解。
Due to the importance of human immunodeficiency virus type 1 (HIV-1) integrase as a drug target, the biochemistry and structural aspects of retroviral DNA integration have been the focus of intensive research during the past three decades. The retroviral integrase enzyme acts on the linear double-stranded viral DNA product of reverse transcription. Integrase cleaves specific phosphodiester bonds near the viral DNA ends during the 3' processing reaction. The enzyme then uses the resulting viral DNA 3'-OH groups during strand transfer to cut chromosomal target DNA, which simultaneously joins both viral DNA ends to target DNA 5'-phosphates. Both reactions proceed via direct transesterification of scissile phosphodiester bonds by attacking nucleophiles: a water molecule for 3' processing, and the viral DNA 3'-OH for strand transfer. X-ray crystal structures of prototype foamy virus integrase-DNA complexes revealed the architectures of the key nucleoprotein complexes that form sequentially during the integration process and explained the roles of active site metal ions in catalysis. X-ray crystallography furthermore elucidated the mechanism of action of HIV-1 integrase strand transfer inhibitors, which are currently used to treat AIDS patients, and provided valuable insights into the mechanisms of viral drug resistance.