Wielens Jerome, Crosby Ian T, Chalmers David K
Department of Medicinal Chemistry, Monash University, 381 Royal Parade, 3052, Parkville, Vic., Australia.
J Comput Aided Mol Des. 2005 May;19(5):301-17. doi: 10.1007/s10822-005-5256-2.
While the general features of HIV-1 integrase function are understood, there is still uncertainty about the composition of the integration complex and how integrase interacts with viral and host DNA. We propose an improved model of the integration complex based on current experimental evidence including a comparison with the homologous Tn5 transposase containing bound DNA and an analysis of DNA binding sites using Goodford's GRID. Our model comprises a pair of integrase dimers, two strands of DNA to represent the viral DNA ends and a strand of bent DNA representing the host chromosome. In our model, the terminal four base pairs of each of the viral DNA strands interact with the integrase dimer providing the active site, while bases one turn away interact with a flexible loop (residues 186-194) on the second integrase dimer. We propose that residues E152, Q148 and K156 are involved in the specific recognition of the conserved CA dinucleotide and that the active site mobile loop (residues 140-149) stabilises the integration complex by acting as a barrier to separate the two viral DNA ends. In addition, the residues responsible for DNA binding in our model show a high level of amino acid conservation.
虽然HIV-1整合酶功能的一般特征已为人所知，但整合复合物的组成以及整合酶如何与病毒和宿主DNA相互作用仍存在不确定性。我们基于当前的实验证据提出了一种改进的整合复合物模型，包括与含有结合DNA的同源Tn5转座酶进行比较，以及使用古德福德的GRID分析DNA结合位点。我们的模型由一对整合酶二聚体、两条代表病毒DNA末端的DNA链和一条代表宿主染色体的弯曲DNA链组成。在我们的模型中，每条病毒DNA链的末端四个碱基对与提供活性位点的整合酶二聚体相互作用，而相隔一圈的碱基与第二个整合酶二聚体上的一个柔性环（残基186 - 194）相互作用。我们提出，残基E152、Q148和K156参与保守CA二核苷酸的特异性识别，并且活性位点移动环（残基140 - 149）通过作为分隔两个病毒DNA末端的屏障来稳定整合复合物。此外，我们模型中负责DNA结合的残基显示出高度的氨基酸保守性。
