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6a5w
From Proteopedia
FXR-LBD with HNC143 and SRC1
Structural highlights
Function[NR1H4_HUMAN] Ligand-activated transcription factor. Receptor for bile acids such as chenodeoxycholic acid, lithocholic acid and deoxycholic acid. Represses the transcription of the cholesterol 7-alpha-hydroxylase gene (CYP7A1) through the induction of NR0B2 or FGF19 expression, via two distinct mechanisms. Activates the intestinal bile acid-binding protein (IBABP). Activates the transcription of bile salt export pump ABCB11 by directly recruiting histone methyltransferase CARM1 to this locus.[1] [2] [3] [4] [5] [6] [7] [8] Publication Abstract from PubMedNuclear receptor farnesoid X receptor (FXR) functions as the major bile acid (BA) sensor coordinating cholesterol metabolism, lipid homeostasis and absorption of dietary fats and vitamins. Because of its central role in metabolism, FXR represents an important drug target to manage metabolic and other diseases, such as primary biliary cirrhosis and non-alcoholic steatohepatitis. FXR and nuclear receptor retinoid X receptor alpha (RXRalpha) form a heterodimer that controls the expression of numerous downstream genes. To date, the structural basis and functional consequences of the FXR/RXR heterodimer interaction have remained unclear. Herein, we present the crystal structures of the heterodimeric complex formed between the ligand-binding domains of human FXR and RXRalpha. We show that both FXR and RXR bind to the transcriptional coregulator steroid receptor coactivator 1 (SRC1) with higher affinity when they are part of the heterodimer complex than when they are in their respective monomeric states. Furthermore, structural comparisons of the FXR/RXRalpha heterodimers and the FXR monomers bound with different ligands indicated that both heterodimerization and ligand binding induce a conformational change in the C terminus of helix 11 in FXR that affects the stability of the coactivator binding surface and the coactivator binding in FXR. In summary, our findings shed light on the allosteric signal transduction in the FXR/RXR heterodimer, which may be utilized for future drug development targeting FXR. Ligand binding and heterodimerization with retinoid X receptor alpha (RXRalpha) induce farnesoid X receptor (FXR) conformational changes affecting co-activator binding.,Wang N, Zou Q, Xu J, Zhang J, Liu J J Biol Chem. 2018 Oct 1. pii: RA118.004652. doi: 10.1074/jbc.RA118.004652. PMID:30275017[9] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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Categories: Human | Liu, J | Wang, N | Agonist | Coactivator | Complex | Nuclear receptor | Transcription
