Abstract
Understanding the nature of allostery in DNA-nuclear receptor (NR) complexes is of fundamental importance for drug development since NRs regulate the transcription of a myriad of genes in humans and other metazoans. Here, we investigate allostery in the peroxisome proliferator-activated/retinoid X receptor heterodimer. This important NR complex is a target for antidiabetic drugs since it binds to DNA and functions as a transcription factor essential for insulin sensitization and lipid metabolism. We find evidence of interdependent motions of Ω-loops and PPARγ-DNA binding domain with contacts susceptible to conformational changes and mutations, critical for regulating transcriptional functions in response to sequence-dependent DNA dynamics. Statistical network analysis of the correlated motions, observed in molecular dynamics simulations, shows preferential allosteric pathways with convergence centers comprised of polar amino acid residues. These findings are particularly relevant for the design of allosteric modulators of ligand-dependent transcription factors.
Highlights
Understanding the nature of allostery in DNA-nuclear receptor (NR) complexes is of fundamental importance for drug development since nuclear receptors (NRs) regulate the transcription of a myriad of genes in humans and other metazoans
We have elucidated the allosteric pathways in DNA-nuclear receptor (NR) complexes, based on the first X-ray structure of a full-length DNA/NR complex
The analysis of correlated motions in the DNA/PPARγ -RXRα complex and in the isolated PPARγ -Ligand Binding Domain (LBD) monomer reveals highly correlated motions between distant mobile regions of the complex, with the most prominent inter-domain correlations found at the conformationally flexible hinges, Ω -loops and helices that participate in dimerization contacts (H9/10) of PPARγ -DNA Binding Domain (DBD)
Summary
Understanding the nature of allostery in DNA-nuclear receptor (NR) complexes is of fundamental importance for drug development since NRs regulate the transcription of a myriad of genes in humans and other metazoans. Ligand-induced activation is dependent on the anchoring DNA sequence[20,21] These studies support the existence of synergism and communication between DBDs, LBDs and DNA, significant structural differences between isolated, complexed domains and DNA bound dimers have not been detected that could explain such behavior, suggesting that dynamic or ensemble allostery might play a role in NRs function. In the permissive type of heterodimers – in which the RXR fully retains its ability to bind ligands – occupancy of RXR’s binding pocket leads to activation of the other NR subunit, either in the absence (transactivation) or in the presence of its own bona fide ligand (synergism)[17,23,24,25], which supports the existence of functional inter-LBD cooperation The latter scenario is common to Peroxisome Proliferator-Activated Receptors (PPARs), which are activated by 9-cis-retinoic acid (RTAC) as well as by their own ligands (e.g., fibrate drugs, thiazolidinediones and fatty acid derivatives from diet and metabolism)[8,24,26]. PPARs are expressed as three subtypes (α , γ , and δ ) with distinct www.nature.com/scientificreports/
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
