4XT2

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

Summary for 4XT2

• Entry DOI: 10.2210/pdb4xt2/pdb
• Related: 3F1O 3F1P 3H82 3HW7 4GHI 4GS9 4LPZ
• Descriptor: Aryl hydrocarbon receptor nuclear translocator, Endothelial PAS domain-containing protein 1, (5S,7R)-5,7-bis(3-bromophenyl)-4,5,6,7-tetrahydrotetrazolo[1,5-a]pyrimidine, ... (4 entities in total)
• Functional Keywords: transcription factor, hypoxia inducible factor, inhibitor, cancer, transcription
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 4
• Total formula weight: 56433.03

Authors

Scheuermann, T.H.,Gardner, K.H. (deposition date: 2015-01-22, release date: 2015-12-09, Last modification date: 2023-09-27)

Primary citation

Scheuermann, T.H.,Stroud, D.,Sleet, C.E.,Bayeh, L.,Shokri, C.,Wang, H.,Caldwell, C.G.,Longgood, J.,MacMillan, J.B.,Bruick, R.K.,Gardner, K.H.,Tambar, U.K.
Isoform-Selective and Stereoselective Inhibition of Hypoxia Inducible Factor-2.
J.Med.Chem., 58:5930-5941, 2015

PubMed Abstract: Hypoxia inducible factor (HIF) transcription factors reside at the center of signaling pathways used by mammalian cells to sense and respond to low oxygen levels. While essential to maintain oxygen homeostasis, misregulation of HIF protein activity correlates with tumor development and metastasis. To provide artificial routes to target misregulated HIF activity, we identified small molecule antagonists of the HIF-2 transcription factor that bind an internal cavity within the C-terminal PAS domain of the HIF-2α subunit. Here we describe a new class of chiral small molecule ligands that provide the highest affinity binding, the most effective, isoform-selective inhibition of HIF-2 in cells, and trigger the largest protein conformation changes reported to date. The current results further illuminate the molecular mechanism of HIF-2 antagonism and suggest additional routes to develop higher affinity and potency HIF-2 antagonists.

PubMed: 26226049
DOI: 10.1021/acs.jmedchem.5b00529

Experimental method

X-RAY DIFFRACTION (1.698 Å)