Marine College, Shandong University, Weihai 264209, China; Helmholtz International Lab, State Key Laboratory of Microbial Technology, Shandong University, Qingdao 266237, China.
Helmholtz International Lab, State Key Laboratory of Microbial Technology, Shandong University, Qingdao 266237, China.
J Mol Biol. 2024 Feb 1;436(3):168352. doi: 10.1016/j.jmb.2023.168352. Epub 2023 Nov 5.
The mammalian family of basic helix-loop-helix-PER-ARNT-SIM (bHLH-PAS) transcription factors possess the ability to sense and respond to diverse environmental and physiological cues. These proteins all share a common structural framework, comprising a bHLH domain, two PAS domains, and transcriptional activation or repression domain. To function effectively as transcription factors, members of the family must form dimers, bringing together bHLH segments to create a functional unit that allows for DNA response element binding. The significance of bHLH-PAS family is underscored by their involvement in many major human diseases, offering potential avenues for therapeutic intervention. Notably, the clear identification of ligand-binding cavities within their PAS domains enables the development of targeted small molecules. Two examples are Belzutifan, targeting hypoxia-inducible factor (HIF)-2α, and Tapinarof, targeting the aryl hydrocarbon receptor (AHR), both of which have gained regulatory approval recently. Here, we focus on the HIF subfamily. The crystal structures of all three HIF-α proteins have been elucidated, revealing their bHLH and tandem PAS domains are used to engage their dimerization partner aryl hydrocarbon receptor nuclear translocator (ARNT, also called HIF-1β). A broad range of recent findings point to a shared allosteric modulation mechanism among these proteins, whereby small-molecules at the PAS-B domains exert direct influence over the HIF-α transcriptional functions. As our understanding of the architectural and allosteric mechanisms of bHLH-PAS proteins continues to advance, the possibility of discovering new therapeutic drugs becomes increasingly promising.
哺乳动物基本螺旋-环-螺旋转录因子家族（bHLH-PAS）具有感知和响应各种环境和生理线索的能力。这些蛋白质都具有共同的结构框架，包括 bHLH 结构域、两个 PAS 结构域和转录激活或抑制结构域。为了有效地作为转录因子发挥作用，家族成员必须形成二聚体，将 bHLH 片段聚集在一起，形成一个允许 DNA 反应元件结合的功能单元。bHLH-PAS 家族的重要性在于它们参与了许多人类重大疾病，为治疗干预提供了潜在途径。值得注意的是，它们 PAS 结构域内配体结合腔的明确鉴定使靶向小分子的开发成为可能。其中两个例子是贝伐单抗（Belzutifan），针对缺氧诱导因子（HIF）-2α，和 Tapinarof，针对芳香烃受体（AHR），两者最近都获得了监管批准。在这里，我们重点关注 HIF 亚家族。已经阐明了所有三种 HIF-α 蛋白质的晶体结构，揭示了它们的 bHLH 和串联 PAS 结构域用于与它们的二聚体伙伴芳香烃受体核转位因子（ARNT，也称为 HIF-1β）结合。最近的大量发现指向这些蛋白质之间共享的变构调节机制，即 PAS-B 结构域的小分子对 HIF-α 转录功能施加直接影响。随着我们对 bHLH-PAS 蛋白质的结构和变构机制的理解不断深入，发现新的治疗药物的可能性变得越来越有希望。
