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Get PDFThe neuronal PAS domain proteins NPAS1 and NPAS3 are members of the basic helix-loop-helix-PER-ARNT-SIM (bHLH-PAS) family, and their genetic deficiencies are linked to a variety of human psychiatric disorders including schizophrenia, autism spectrum disorders and bipolar disease. NPAS1 and NPAS3 must each heterodimerize with the aryl hydrocarbon receptor nuclear translocator (ARNT), to form functional transcription complexes capable of DNA binding and gene regulation. Here we examined the crystal structures of multi-domain NPAS1-ARNT and NPAS3-ARNT-DNA complexes, discovering each to contain four putative ligand-binding pockets. Through expanded architectural comparisons between these complexes and HIF-1α-ARNT, HIF-2α-ARNT and CLOCK-BMAL1, we show the wider mammalian bHLH-PAS family is capable of multi-ligand-binding and presents as an ideal class of transcription factors for direct targeting by small-molecule drugs.sponsorship: [
"National Institutes of Health NIGMS 1R01GM117013 Fraydoon Rastinejad",
"Army Research Office W81XWH-16-1-0322 Fraydoon Rastinejad"
] (National Institutes of Health|NIGMS 1R01GM117013, Army Research Office|W81XWH-16-1-0322)status: Publishe
The protein architecture and allosteric landscape of HNF4α
Get PDFHepatocyte nuclear factor 4 alpha (HNF4α) is a multi-faceted nuclear receptor responsible for governing the development and proper functioning of liver and pancreatic islet cells. Its transcriptional functions encompass the regulation of vital metabolic processes including cholesterol and fatty acid metabolism, and glucose sensing and control. Various genetic mutations and alterations in HNF4α are associated with diabetes, metabolic disorders, and cancers. From a structural perspective, HNF4α is one of the most comprehensively understood nuclear receptors due to its crystallographically observed architecture revealing interconnected DNA binding domains (DBDs) and ligand binding domains (LBDs). This review discusses key properties of HNF4α, including its mode of homodimerization, its binding to fatty acid ligands, the importance of post-translational modifications, and the mechanistic basis for allosteric functions. The surfaces linking HNF4α’s DBDs and LBDs create a convergence zone that allows signals originating from any one domain to influence distant domains. The HNF4α-DNA complex serves as a prime illustration of how nuclear receptors utilize individual domains for specific functions, while also integrating these domains to create cohesive higher-order architectures that allow signal responsive functions
Retinoid X receptor and its partners in the nuclear receptor family
No full textRetinoid X receptor (RXR) and its dimerization partners in the nuclear receptor family recognize DNA response elements in which two AGGTCA binding sites are arranged in tandem. Target site selection by these complexes requires the spacing between the binding sites to act as the identity element. With the recent determination of three-dimensional structures of several different DNA-binding complexes of RXR, together with studies of protein conformational changes, it is clear how the interactions of RXR with its partners are precisely tuned to match the spacing between their DNA binding sites.status: Publishe
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