The structure of HIV-1 reverse transcriptase complexed with 9-chloro-TIBO: lessons for inhibitor design.
The structure of HIV-1 reverse transcriptase complexed with 9-chloro-TIBO: lessons for inhibitor design.
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DOI：
10.1016/s0969-2126(01)00226-x
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发表时间：
1995-09
期刊：
影响因子：
5.7
通讯作者：
Jingshan Ren;R. Esnouf;Andrew Hopkins;C. Ross;Y. Jones;D. Stammers;D. Stuart
中科院分区：
文献类型：
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作者：
Jingshan Ren;R. Esnouf;Andrew Hopkins;C. Ross;Y. Jones;D. Stammers;D. Stuart
背景：HIV逆转录酶（RT）是抗艾滋病治疗的关键靶点。 HIV-1 RT（未配体和与不同非核苷抑制剂 (NNI) 复合）的结构研究指出，通过含有两个铰接环的 NNI 扭曲聚合酶催化位点，可以实现结合和失活的常见模式。 TIBO 抑制剂家族的结合模式令人感兴趣，因为这些化合物不符合双铰链模型。结果 HIV-1 RT 与 9-氯-TIBO (R82913) 复合的结构已在 2.6 α 分辨率下确定。正如对另一种 TIBO 化合物的较低分辨率分析所报道的那样，该抑制剂与其他 NNI 结合在同一位点，但我们的高分辨率研究表明，Cl-TIBO 与单独抑制剂晶体中看到的构象不同。这使得 Cl-TIBO 能够模拟包含两个铰链环的 NNI 的结合。抑制剂-蛋白质相互作用同样主要是疏水性的，并且蛋白质构象与在与其他紧密结合的 NNI 的复合物中看到的相对应。结论尽管 Cl-TIBO 在化学上与其他 NNI 非常不同，但它在与 RT 结合时与其他 NNI 实现了显着的空间等效性和形状互补性。不同 RT-NNI 复合物的比较表明对 TIBO 抑制剂组的修饰可能会增强它们的结合，从而可能增强它们的治疗功效。
Background:HIV reverse transcriptase (RT) is a key target of anti-AIDS therapies. Structural studies of HIV-1 RT, unliganded and complexed with different non-nucleoside inhibitors (NNIs), have pointed to a common mode of binding and inactivation through distortion of the polymerase catalytic site by NNIs containing two hinged rings. The mode of binding of the TIBO family of inhibitors is of interest because these compounds do not fit the two-hinged-ring model.ResultsThe structure of HIV-1 RT complexed with 9-chloro-TIBO (R82913) has been determined at 2.6 å resolution. As reported for the lower resolution analysis of another TIBO compound, this inhibitor binds at the same site as other NNIs, but our higher resolution study reveals the Cl-TIBO is distorted from the conformation seen in crystals of the inhibitor alone. This allows Cl-TIBO to mimic the binding of NNIs containing two hinged rings. Inhibitor–protein interactions are again predominantly hydrophobic and the protein conformation corresponds to that seen in complexes with other tight-binding NNIs.ConclusionAlthough Cl-TIBO is chemically very different from other NNIs, it achieves remarkable spatial equivalence and shape complementarity with other NNIs on binding to RT. Comparison of the different RT–NNI complexes suggests modifications to the TIBO group of inhibitors which might enhance their binding and hence, potentially, their therapeutic efficacy.