9LOI

Crystal Structure of the Heterodimeric HIF-2 Complex with Agonist SD-16

This is a non-PDB format compatible entry.

Summary for 9LOI

• Entry DOI: 10.2210/pdb9loi/pdb
• Descriptor: Aryl hydrocarbon receptor nuclear translocator, Endothelial PAS domain-containing protein 1, 6-chloranyl-1,1-bis(oxidanylidene)-~{N}-(2-pyrrolidin-1-ylphenyl)-1,2-benzothiazol-3-amine, ... (4 entities in total)
• Functional Keywords: hypoxia-inducible factor (hif)-2, transcriptor, transcription
• Biological source: Mus musculus (house mouse); More
• Total number of polymer chains: 2
• Total formula weight: 86071.33

Authors

Wu, D.,Zhuang, J.,Li, F.,Chen, X.,Diao, X. (deposition date: 2025-01-23, release date: 2025-10-15, Last modification date: 2025-11-05)

Primary citation

Guo, M.,Xu, W.,Bai, Z.,Chen, K.,Li, F.,Jin, Z.,Chen, X.,Shang, Q.,Zhang, M.,Diao, X.,Xu, D.,Zhang, H.,Mu, K.,Wang, Y.,Ly, T.,Li, L.,Zhu, Y.,Song, C.,Zhao, H.,Wan, X.,Zhang, Y.,Zhuang, J.,Wu, D.
Structure-Based Optimization of HIF-2 alpha Agonists That Synergistically Enhance Erythropoietin Production with PHD Inhibitors.
J.Med.Chem., 68:21346-21365, 2025

PubMed Abstract: Hypoxia-inducible factor 2α (HIF-2α) is a crucial transcription factor regulating various physiological processes, including angiogenesis and erythropoiesis. The activity of HIF-2α is mainly controlled through oxygen-dependent protein hydroxylation, mediated by prolyl hydroxylase domain (PHD) enzymes, leading to subsequent HIF-2α ubiquitination and degradation. While several small-molecule PHD inhibitors have already been clinically applied in renal anemia treatment by indirectly activating the HIF-2α pathway, direct HIF-2α agonists remain largely unexplored. Here, we developed derivatives of HIF-2α agonist M1001, identifying through molecular/cellular evaluations. By determining its cocrystal structure with the heterodimeric HIF-2 protein complex, we precisely characterized its molecular mechanism of action. Notably, exhibited remarkable synergy with Daprodustat, an approved PHD inhibitor, in stimulating erythropoietin (EPO) secretion both in cellular models and animal studies. These findings not only provide insights into HIF-2α activation mechanism, but also offer a promising lead compound for developing innovative treatments for renal anemia.

PubMed: 41047546
DOI: 10.1021/acs.jmedchem.5c01257

Experimental method

X-RAY DIFFRACTION (2.78 Å)