6E3S

Crystal Structure of the Heterodimeric HIF-2 Complex with Antagonist PT2385

6E3S の概要

• エントリーDOI: 10.2210/pdb6e3s/pdb
• 分子名称: Aryl hydrocarbon receptor nuclear translocator, Endothelial PAS domain-containing protein 1, 3-{[(1S)-2,2-difluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl]oxy}-5-fluorobenzonitrile (3 entities in total)
• 機能のキーワード: complex, antagonist, transcription factor, transcription-transcription inhibitor complex, transcription/transcription inhibitor
• 由来する生物種: Mus musculus (Mouse); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 85977.69

構造登録者

Wu, D.,Su, X.,Lu, J.,Li, S.,Hood, B.,Vasile, S.,Potluri, N.,Diao, X.,Kim, Y.,Khorasanizadeh, S.,Rastinejad, F. (登録日: 2018-07-15, 公開日: 2019-02-13, 最終更新日: 2023-10-11)

主引用文献

Wu, D.,Su, X.,Lu, J.,Li, S.,Hood, B.L.,Vasile, S.,Potluri, N.,Diao, X.,Kim, Y.,Khorasanizadeh, S.,Rastinejad, F.
Bidirectional modulation of HIF-2 activity through chemical ligands.
Nat. Chem. Biol., 15:367-376, 2019

PubMed Abstract: 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.

PubMed: 30804532
DOI: 10.1038/s41589-019-0234-5

実験手法

X-RAY DIFFRACTION (3 Å)