The general transcription factor II H (TFIIH) plays an essential role in transcription and nucleotide excision DNA repair (NER). TFIIH is a complex 10 subunit containing molecular machine that harbors three enzymatic activities while the remaining subunits assume regulatory and/or structural functions. Intriguingly, the three enzymatic activities of the CDK7 kinase, the XPB translocase, and the XPD helicase exert different impacts on the overall activities of TFIIH. While the enzymatic function of the XPD helicase is exclusively required in NER, the CDK7 kinase is deeply involved in transcription, whereas XPB is essential to both processes. Recent structural and biochemical endeavors enabled unprecedented details towards the molecular basis of these different TFIIH functions and how the enzymatic activities are regulated within the entire complex. Due to its involvement in two fundamental processes, TFIIH has become increasingly important as a target in cancer therapy and two of the three enzymes have already been addressed successfully. Here we explore the possibilities of recent high resolution structures in the context of TFIIH druggability and shed light on the functional consequences of the different approaches towards TFIIH inhibition.

一般转录因子 II H (TFIIH) 在转录和核苷酸切除 DNA 修复 (NER) 中起重要作用。TFIIH 是一个复杂的 10 个亚基，包含分子机器，具有三种酶活性，而其余亚基承担调节和/或结构功能。有趣的是，CDK7 激酶、XPB 转位酶和 XPD 解旋酶的三种酶活性对 TFIIH 的整体活性产生不同的影响。虽然 NER 只需要 XPD 解旋酶的酶促功能，但 CDK7 激酶深入参与转录，而 XPB 对这两个过程都必不可少。最近的结构和生化努力使得对这些不同 TFIIH 功能的分子基础以及酶活性如何在整个复合物内进行调节提供了前所未有的细节。由于其参与两个基本过程，TFIIH 作为癌症治疗的靶点变得越来越重要，并且三种酶中的两种已经成功解决。在这里，我们在 TFIIH 成药性的背景下探索了最近高分辨率结构的可能性，并阐明了不同方法对 TFIIH 抑制的功能后果。