4GHI

Crystal structure of the high affinity heterodimer of HIF2 alpha and ARNT C-terminal PAS domains in complex with a benzoxadiazole antagonist

4GHI の概要

• エントリーDOI: 10.2210/pdb4ghi/pdb
• 関連するPDBエントリー: 2HV1 3F1N 3F1O 3F1P 3H7W 3H82
• 分子名称: Endothelial PAS domain-containing protein 1, Aryl hydrocarbon receptor nuclear translocator, N-(3-chloro-5-fluorophenyl)-4-nitro-2,1,3-benzoxadiazol-5-amine, ... (4 entities in total)
• 機能のキーワード: pas fold, protein : protein interactions, transcription
• 由来する生物種: Homo sapiens (human); 詳細
• 細胞内の位置: Nucleus (Potential): Q99814; Nucleus: P27540
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 28090.05

構造登録者

Scheuermann, T.H.,Key, J.,Tambar, U.K.,Bruick, R.K.,Gardner, K.H. (登録日: 2012-08-07, 公開日: 2013-02-27, 最終更新日: 2023-09-13)

主引用文献

Scheuermann, T.H.,Li, Q.,Ma, H.W.,Key, J.,Zhang, L.,Chen, R.,Garcia, J.A.,Naidoo, J.,Longgood, J.,Frantz, D.E.,Tambar, U.K.,Gardner, K.H.,Bruick, R.K.
Allosteric inhibition of hypoxia inducible factor-2 with small molecules.
Nat.Chem.Biol., 9:271-276, 2013

PubMed Abstract: Hypoxia inducible factors (HIFs) are heterodimeric transcription factors induced in many cancers where they frequently promote the expression of protumorigenic pathways. Though transcription factors are typically considered 'undruggable', the PAS-B domain of the HIF-2α subunit contains a large cavity within its hydrophobic core that offers a unique foothold for small-molecule regulation. Here we identify artificial ligands that bind within this pocket and characterize the resulting structural and functional changes caused by binding. Notably, these ligands antagonize HIF-2 heterodimerization and DNA-binding activity in vitro and in cultured cells, reducing HIF-2 target gene expression. Despite the high sequence identity between HIF-2α and HIF-1α, these ligands are highly selective and do not affect HIF-1 function. These chemical tools establish the molecular basis for selective regulation of HIF-2, providing potential therapeutic opportunities to intervene in HIF-2-driven tumors, such as renal cell carcinomas.

PubMed: 23434853
DOI: 10.1038/nchembio.1185

実験手法

X-RAY DIFFRACTION (1.5 Å)