Helmholtz International Lab, State Key Laboratory of Microbial Technology, Shandong University, Qingdao, China.
Integrative Metabolism Program, Sanford Burnham Prebys Medical Discovery Institute, Orlando, FL, USA.
Nat Chem Biol. 2019 Apr;15(4):367-376. doi: 10.1038/s41589-019-0234-5. Epub 2019 Feb 25.
Hypoxia-inducible factor-2 (HIF-2) is a heterodimeric transcription factor formed through dimerization between an oxygen-sensitive HIF-2α subunit and its obligate partner subunit ARNT. Enhanced HIF-2 activity drives some cancers, whereas reduced activity causes anemia in chronic kidney disease. Therefore, modulation of HIF-2 activity via direct-binding ligands could provide many new therapeutic benefits. Here, we explored HIF-2α chemical ligands using combined crystallographic, biophysical, and cell-based functional studies. We found chemically unrelated antagonists to employ the same mechanism of action. Their binding displaced residue M252 from inside the HIF-2α PAS-B pocket toward the ARNT subunit to weaken heterodimerization. We also identified first-in-class HIF-2α agonists and found that they significantly displaced pocket residue Y281. Its dramatic side chain movement increases heterodimerization stability and transcriptional activity. Our findings show that despite binding to the same HIF-2α PAS-B pocket, ligands can manifest as inhibitors versus activators by mobilizing different pocket residues to allosterically alter HIF-2α-ARNT heterodimerization.
缺氧诱导因子-2（HIF-2）是一种异二聚体转录因子，通过氧敏感的 HIF-2α 亚基与其必需的伴侣亚基 ARNT 之间的二聚化形成。增强的 HIF-2 活性驱动一些癌症，而慢性肾病中的活性降低会导致贫血。因此，通过直接结合配体来调节 HIF-2 活性可能会带来许多新的治疗益处。在这里，我们使用组合晶体学、生物物理和基于细胞的功能研究来探索 HIF-2α 的化学配体。我们发现化学上不相关的拮抗剂采用相同的作用机制。它们的结合将残基 M252 从 HIF-2α PAS-B 口袋内部推向 ARNT 亚基，从而削弱异二聚化。我们还鉴定了一类新型的 HIF-2α 激动剂，并发现它们显著取代口袋残基 Y281。其剧烈的侧链运动增加了异二聚体的稳定性和转录活性。我们的研究结果表明，尽管结合到相同的 HIF-2α PAS-B 口袋，但配体可以通过动员不同的口袋残基来改变 HIF-2α-ARNT 异二聚化，从而表现为抑制剂或激动剂。
