The human CDK-activating kinase (CAK), composed of CDK7, cyclin H, and MAT1, is involved in the control of transcription initiation and the cell cycle. Due to these activities, it has been identified as a promising target for cancer chemotherapy. A number of CDK7 inhibitors have entered clinical trials, among them ICEC0942 (also known as CT7001). Structural information can aid to improve the affinity and specificity of such drugs or drug candidates, reducing side effects in patients. Here, we have determined the structure of the human CAK in complex with ICEC0942 at 2.5 Å resolution using cryo-electron microscopy (cryo-EM). Our structure reveals conformational differences of ICEC0942 compared to previous X-ray crystal structures of the CDK2-bound complex, highlighting the critical ability of cryo-EM to resolve structures of drug-bound protein complexes without the need to crystalize the protein target.

中文翻译：

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与临床抑制剂 ICEC0942 结合的人 CDK 激活激酶的 2.5Å 分辨率结构


人类 CDK 激活激酶 (CAK) 由 CDK7、细胞周期蛋白 H 和 MAT1 组成，参与转录起始和细胞周期的控制。由于这些活性，它已被确定为癌症化疗的有希望的靶标。多个CDK7抑制剂已进入临床试验，其中包括ICEC0942（也称为CT7001）。结构信息有助于提高此类药物或候选药物的亲和力和特异性，减少患者的副作用。在这里，我们使用冷冻电子显微镜 (cryo-EM) 以 2.5 Å 的分辨率确定了人类 CAK 与 ICEC0942 复合物的结构。我们的结构揭示了 ICEC0942 与之前 CDK2 结合复合物的 X 射线晶体结构相比的构象差异，突出了冷冻电镜在无需结晶蛋白质靶标的情况下解析药物结合蛋白复合物结构的关键能力。