5ufp
From Proteopedia
Crystal structure of PT2399 bound to HIF2a-B*:ARNT-B* complex
Structural highlights
Disease[EPAS1_HUMAN] Defects in EPAS1 are the cause of familial erythrocytosis type 4 (ECYT4) [MIM:611783]. ECYT4 is an autosomal dominant disorder characterized by increased serum red blood cell mass, elevated hemoglobin concentration and hematocrit, and normal platelet and leukocyte counts.[1] [2] [3] [4] Function[EPAS1_HUMAN] Transcription factor involved in the induction of oxygen regulated genes. Binds to core DNA sequence 5'-[AG]CGTG-3' within the hypoxia response element (HRE) of target gene promoters. Regulates the vascular endothelial growth factor (VEGF) expression and seems to be implicated in the development of blood vessels and the tubular system of lung. May also play a role in the formation of the endothelium that gives rise to the blood brain barrier. Potent activator of the Tie-2 tyrosine kinase expression. Activation seems to require recruitment of transcriptional coactivators such as CREBPB and probably EP300. Interaction with redox regulatory protein APEX seems to activate CTAD. [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 PubMedClear cell renal cell carcinoma (ccRCC), the most common form of kidney cancer, is usually linked to inactivation of the pVHL tumor suppressor protein and consequent accumulation of the HIF2alpha transcription factor 1. Here we show that a small molecule (PT2399) that directly inhibits HIF2alpha causes tumor regression in preclinical models of primary and metastatic pVHL-defective ccRCC in an on-target fashion. pVHL-defective ccRCC cell lines display unexpectedly variable sensitivity to PT2399, however, suggesting the need for predictive biomarkers. On-Target Efficacy of a HIF2alpha Antagonist in Preclinical Kidney Cancer Models.,Cho H, Du X, Rizzi JP, Liberzon E, Chakraborty AA, Gao W, Carvo I, Signoretti S, Bruick R, Josey JA, Wallace EM, Kaelin WG Jr Nature. 2016 Sep 5. doi: 10.1038/nature19795. PMID:27595393[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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