Bidirectional modulation of HIF-2 activity through chemical ligands

Wu, Dalei; Su, Xiaoyu; Lu, Jingping; Li, Sheng; Hood, Becky L.; Vasile, Stefan; Potluri, Nalini; Diao, Xiaotong; Kim, Youngchang; Khorasanizadeh, Sepideh; Rastinejad, Fraydoon

doi:10.1038/s41589-019-0234-5

Title: Bidirectional modulation of HIF-2 activity through chemical ligands

Journal Article · Mon Apr 01 00:00:00 EDT 2019 · Nature Chemical Biology

DOI:https://doi.org/10.1038/s41589-019-0234-5· OSTI ID:1514883

Wu, Dalei; Su, Xiaoyu; Lu, Jingping; Li, Sheng; Hood, Becky L.; Vasile, Stefan; Potluri, Nalini; Diao, Xiaotong; Kim, Youngchang; Khorasanizadeh, Sepideh; Rastinejad, Fraydoon

Hypoxia-inducible factor-2 (HIF-2) is a heterodimeric transcription factor formed through dimerization between an oxygen-sensitive HIF-2 alpha 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-2 alpha 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-2 alpha PAS-B pocket toward the ARNT subunit to weaken heterodimerization. We also identified first-in-class HIF-2 alpha 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-2 alpha PAS-B pocket, ligands can manifest as inhibitors versus activators by mobilizing different pocket residues to allosterically alter HIF-2 alpha-ARNT heterodimerization.

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Research Organization:: Argonne National Lab. (ANL), Argonne, IL (United States)

Sponsoring Organization:: USDOE Office of Science - Office of Biological and Environmental Research; National Institutes of Health (NIH); Shandong University; National Natural Science Foundation of China (NSFC); National Natural Science Foundation of Jiangsu Province; Wellcome Trust; U.S. Army Research Laboratory

DOE Contract Number:: AC02-06CH11357

OSTI ID:: 1514883

Journal Information:: Nature Chemical Biology, Vol. 15, Issue 4

Country of Publication:: United States

Language:: English

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