4J5X

Crystal Structure of the SR12813-bound PXR/RXRalpha LBD Heterotetramer Complex

Summary for 4J5X

• Entry DOI: 10.2210/pdb4j5x/pdb
• Related: 4J5W
• Descriptor: Retinoic acid receptor RXR-alpha, Nuclear receptor coactivator 1, Nuclear receptor subfamily 1 group I member 2, Nuclear receptor coactivator 1, [2-(3,5-DI-TERT-BUTYL-4-HYDROXY-PHENYL)-1-(DIETHOXY-PHOSPHORYL)-VINYL]-PHOSPHONIC ACID DIETHLYL ESTER, ... (4 entities in total)
• Functional Keywords: pregnane x receptor, retinoid x receptor alpha, ligand binding domain, nuclear receptor, sr12813, alpha helical sandwich, unique intermolecular beta-sheet dimerization, xenobiotic sensing, upregulation of drug metabolism enzymes, retinoic acid-binding protein
• Biological source: Homo sapiens (human); More
• Cellular location: Nucleus : Q15788 Q15788
• Total number of polymer chains: 4
• Total formula weight: 136082.34

Authors

Wallace, B.D.,Betts, L.,Redinbo, M.R. (deposition date: 2013-02-10, release date: 2013-08-21, Last modification date: 2024-02-28)

Primary citation

Wallace, B.D.,Betts, L.,Talmage, G.,Pollet, R.M.,Holman, N.S.,Redinbo, M.R.
Structural and Functional Analysis of the Human Nuclear Xenobiotic Receptor PXR in Complex with RXRalpha.
J.Mol.Biol., 425:2561-2577, 2013

PubMed Abstract: The human nuclear xenobiotic receptor PXR recognizes a range of potentially harmful drugs and endobiotic chemicals but must complex with the nuclear receptor RXRα to control the expression of numerous drug metabolism genes. To date, the structural basis and functional consequences of this interaction have remained unclear. Here we present 2.8-Å-resolution crystal structures of the heterodimeric complex formed between the ligand-binding domains of human PXR and RXRα. These structures establish that PXR and RXRα form a heterotetramer unprecedented in the nuclear receptor family of ligand-regulated transcription factors. We further show that both PXR and RXRα bind to the transcriptional coregulator SRC-1 with higher affinity when they are part of the PXR/RXRα heterotetramer complex than they do when each ligand-binding domain is examined alone. Furthermore, we purify the full-length forms of each receptor from recombinant bacterial expression systems and characterize their interactions with a range of direct and everted repeat DNA elements. Taken together, these data advance our understanding of PXR, the master regulator of drug metabolism gene expression in humans, in its functional partnership with RXRα.

PubMed: 23602807
DOI: 10.1016/j.jmb.2013.04.012

Experimental method

X-RAY DIFFRACTION (2.8 Å)