4xt2

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

Structural highlights

4xt2 is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.698Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

ARNT_HUMAN Required for activity of the Ah (dioxin) receptor. This protein is required for the ligand-binding subunit to translocate from the cytosol to the nucleus after ligand binding. The complex then initiates transcription of genes involved in the activation of PAH procarcinogens. The heterodimer with HIF1A or EPAS1/HIF2A functions as a transcriptional regulator of the adaptive response to hypoxia.

Publication Abstract from PubMed

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-2alpha 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.

Isoform-Selective and Stereoselective Inhibition of Hypoxia Inducible Factor-2.,Scheuermann TH, Stroud D, Sleet CE, Bayeh L, Shokri C, Wang H, Caldwell CG, Longgood J, MacMillan JB, Bruick RK, Gardner KH, Tambar UK J Med Chem. 2015 Aug 13;58(15):5930-41. doi: 10.1021/acs.jmedchem.5b00529. Epub, 2015 Jul 30. PMID:26226049^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Scheuermann TH, Stroud D, Sleet CE, Bayeh L, Shokri C, Wang H, Caldwell CG, Longgood J, MacMillan JB, Bruick RK, Gardner KH, Tambar UK. Isoform-Selective and Stereoselective Inhibition of Hypoxia Inducible Factor-2. J Med Chem. 2015 Aug 13;58(15):5930-41. doi: 10.1021/acs.jmedchem.5b00529. Epub, 2015 Jul 30. PMID:26226049 doi:http://dx.doi.org/10.1021/acs.jmedchem.5b00529