4GHI
Crystal structure of the high affinity heterodimer of HIF2 alpha and ARNT C-terminal PAS domains in complex with a benzoxadiazole antagonist
Summary for 4GHI
| Entry DOI | 10.2210/pdb4ghi/pdb |
| Related | 2HV1 3F1N 3F1O 3F1P 3H7W 3H82 |
| Descriptor | 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) |
| Functional Keywords | pas fold, protein : protein interactions, transcription |
| Biological source | Homo sapiens (human) More |
| Cellular location | Nucleus (Potential): Q99814 Nucleus: P27540 |
| Total number of polymer chains | 2 |
| Total formula weight | 28090.05 |
| Authors | Scheuermann, T.H.,Key, J.,Tambar, U.K.,Bruick, R.K.,Gardner, K.H. (deposition date: 2012-08-07, release date: 2013-02-27, Last modification date: 2023-09-13) |
| Primary citation | 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 Cited by 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: 23434853DOI: 10.1038/nchembio.1185 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.5 Å) |
Structure validation
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