Structural basis for the recognition between HIV-1 integrase and transcriptional coactivator p75
Structural basis for the recognition between HIV-1 integrase and transcriptional coactivator p75
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DOI：
10.1073/pnas.0506924102
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发表时间：
2005-11-29
影响因子：
11.1
通讯作者：
Engelman, A
中科院分区：
文献类型：
--
作者：
Cherepanov, P;Ambrosio, ALB;Engelman, A
整合酶（IN）是一种必需的逆转录病毒酶，而人转录共激活因子p75（也称为透镜上皮衍生生长因子（LEDGF））是HIV-1 IN的主要细胞结合伴侣。在这里，我们报告的晶体结构的二聚体催化核心结构域的HIV-1 IN复杂的IN结合结构域的LEDGF。先前鉴定的LEDGF热点残基将蛋白质锚到IN晚餐界面处的两个单体。由宿主因子识别的IN的主要结构特征是来自一个单体的残基168-171的主链构象和主要由第二个IN单体的α-螺旋1和3组成的疏水补丁。不同的逆转录病毒一级和二级序列元件的检查有助于解释LEDGF-IN相互作用的明显慢病毒向性。由于HIV-1突变病毒的致死表型不能与LEDGF相互作用，表明IN功能对LEDGF结合位点周围结构的扰动高度敏感，因此我们提出蛋白质-蛋白质相互作用的小分子抑制剂可能同样会破坏HIV-1复制。
Integrase (IN) is an essential retroviral enzyme, and human transcriptional coactivator p75, which is also referred to as lens epithelium-derived growth factor (LEDGF), is the dominant cellular binding partner of HIV-1 IN. Here, we report the crystal structure of the dimeric catalytic core domain of HIV-1 IN complexed to the IN-binding domain of LEDGF. Previously identified LEDGF hotspot residues anchor the protein to both monomers at the IN dinner interface. The principal structural features of IN that are recognized by the host factor are the backbone conformation of residues 168-171 from one monomer and a hydrophobic patch that is primarily comprised of a-helices 1 and 3 of the second IN monomer. inspection of diverse retroviral primary and secondary sequence elements helps to explain the apparent lentiviral tropism of the LEDGF-IN interaction. Because the lethal phenotypes of HIV-1 mutant viruses unable to interact with LEDGF indicate that IN function is highly sensitive to perturbations of the structure around the LEDGF-binding site, we propose that small molecule inhibitors of the protein-protein interaction might similarly disrupt HIV-1 replication.