5kiz
Solution Structure of a repacked version of HIF-2 alpha PAS-B
Structural highlights
DiseaseEPAS1_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] FunctionEPAS1_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. Publication Abstract from PubMedHypoxia-inducible factors (HIFs) are heterodimeric transcription factors central to hypoxia response and cancer development. Within the HIF-2 complex, one domain (HIF-2alpha PAS-B) contains a large (290 A(3)) buried cavity filled with water molecules within its hydrophobic core. Such cavities are uncommon except in the case of ligand-binding proteins, leading to the hypothesis that HIF-2alpha can be regulated by small molecules. The development of artificial HIF-2alpha inhibitors validates this hypothesis but raises questions about the impact of this cavity on HIF-2alpha PAS-B structure and function. To answer these points, we used computational methods to construct a repacked protein containing a smaller cavity within the native fold. Experimental validation of a five-mutation variant confirms achieving these objectives and stabilizing the folded structure. Complementary functional data establish that ligands cannot bind this variant although heterodimerization remains unchanged. Altogether, our strategy innovatively addresses the roles of solvated cavities in maintaining protein stability and function. Computational Repacking of HIF-2alpha Cavity Replaces Water-Based Stabilized Core.,Correa F, Key J, Kuhlman B, Gardner KH Structure. 2016 Nov 1;24(11):1918-1927. doi: 10.1016/j.str.2016.08.014. Epub 2016, Sep 22. PMID:27667693[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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