3E94

Crystal structure of RXRalpha ligand binding domain in complex with tributyltin and a coactivator fragment

Summary for 3E94

• Entry DOI: 10.2210/pdb3e94/pdb
• Related: 1LBD 1XDK 2P1T 2P1U 2P1V
• Descriptor: Retinoic acid receptor RXR-alpha, Nuclear receptor coactivator 2 peptide, tributylstannanyl, ... (5 entities in total)
• Functional Keywords: protein-ligand complex, dna-binding, host-virus interaction, metal-binding, nucleus, polymorphism, receptor, transcription, transcription regulation, ubl conjugation, zinc, zinc-finger, activator, phosphoprotein
• Biological source: Homo sapiens (human); More
• Cellular location: Nucleus: P19793 Q15596
• Total number of polymer chains: 2
• Total formula weight: 29198.48

Authors

Bourguet, W.,Le Maire, A. (deposition date: 2008-08-21, release date: 2009-03-10, Last modification date: 2023-08-30)

Primary citation

le Maire, A.,Grimaldi, M.,Roecklin, D.,Dagnino, S.,Vivat-Hannah, V.,Balaguer, P.,Bourguet, W.
Activation of RXR-PPAR heterodimers by organotin environmental endocrine disruptors
Embo Rep., 10:367-373, 2009

PubMed Abstract: The nuclear receptor retinoid X receptor-alpha (RXR-alpha)-peroxisome proliferator-activated receptor-gamma (PPAR-gamma) heterodimer was recently reported to have a crucial function in mediating the deleterious effects of organotin compounds, which are ubiquitous environmental contaminants. However, because organotins are unrelated to known RXR-alpha and PPAR-gamma ligands, the mechanism by which these compounds bind to and activate the RXR-alpha-PPAR-gamma heterodimer at nanomolar concentrations has remained elusive. Here, we show that tributyltin (TBT) activates all three RXR-PPAR-alpha, -gamma, -delta heterodimers, primarily through its interaction with RXR. In addition, the 1.9 A resolution structure of the RXR-alpha ligand-binding domain in complex with TBT shows a covalent bond between the tin atom and residue Cys 432 of helix H11. This interaction largely accounts for the high binding affinity of TBT, which only partly occupies the RXR-alpha ligand-binding pocket. Our data allow an understanding of the binding and activation properties of the various organotins and suggest a mechanism by which these tin compounds could affect other nuclear receptor signalling pathways.

PubMed: 19270714
DOI: 10.1038/embor.2009.8

Experimental method

X-RAY DIFFRACTION (1.9 Å)