title: Computational studies of LXR molecular interactions reveal an allosteric communication pathway.
abstract: The liver X receptor, LXRα, is an important regulator of genes involved in metabolism and inflammation. The mechanism of communication between the cofactor peptide and the ligand in the ligand-binding pocket is a crucial and often discussed issue for the nuclear receptors (NRs), but such allosteric signaling pathways are difficult to detect and the transmission mechanism remains elusive. Here, we apply the anisotropic thermal diffusion method to the LXRα with bound coactivator and ligand. We detected a possible communication pathway between the coactivator peptide and the ligand. The signal is transmitted both through the receptor backbone and side chains. A key signaling residue is the first leucine in the cofactor peptide recognition motif LXXLL, which is conserved within the NR cofactors, suggesting a general mechanism for allosteric signaling. Furthermore, we studied the LXR receptor and cofactor molecular interactions in detail using molecular dynamics simulations. The protein-protein interaction patterns in the complexes of nine different cofactor peptides and holo-LXRα were characterized, revealing the importance of the receptor-cofactor charge clamp interaction. Specific, but infrequently occurring interactions were observed toward the cofactor peptide C-terminal residues. Thus, additional specificity between LXRα and its cofactors is likely to be found in molecular interactions outside the cofactor peptide or in other biological factors.
authors.affiliation: Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden.
authors.forename: Sofia
authors.initials: S
authors.lastname: Burendahl
authors.forename: Lennart
authors.initials: L
authors.lastname: Nilsson
mesh_terms: D000494:Allosteric Regulation; D000495:Allosteric Site; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D006801:Humans; D006860:Hydrogen Bonding; D000071518:Liver X Receptors; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D056918:Nuclear Receptor Coactivators / Q000737:chemistry; D057093:Orphan Nuclear Receptors / Q000737:chemistry*; D010455:Peptides / Q000737:chemistry; D011485:Protein Binding; D017433:Protein Structure, Secondary; D049230:Retinoid X Receptor beta / Q000737:chemistry; D015398:Signal Transduction
chemical_list: D000071518:Liver X Receptors; C000605213:NR1H3 protein, human; D056918:Nuclear Receptor Coactivators; D057093:Orphan Nuclear Receptors; D010455:Peptides; D049230:Retinoid X Receptor beta