title: Ligand-binding regulation of LXR/RXR and LXR/PPAR heterodimerizations: SPR technology-based kinetic analysis correlated with molecular dynamics simulation.
abstract: Liver X receptor (LXR) and peroxisome proliferator-activated receptor (PPAR) are two members of nuclear receptors involved in the nutrient metabolisms of dietary fatty acid and cholesterol. They are found to be of cross-talk function in that LXR regulates fatty acid synthesis and PPAR controls fatty acid degradation. LXRs (LXRalpha and LXRbeta) function by forming obligate heterodimers with the retinoid X receptor (RXR), and subsequently binding to specific DNA response elements within the regulatory regions of their target genes. In this work, the kinetic features concerning LXR/RXR and LXR/PPAR interactions have been fully investigated using surface plasmon resonance (SPR) technology. It is found that LXRs could bind to all the three PPAR subtypes, PPARalpha, PPARgamma and PPARdelta with different binding affinities, and such receptor/receptor interactions could be regulated by ligand binding. Moreover, molecular dynamics (MD) simulations were performed on six typical complex models. The results revealed that ligands may increase the interaction energies between the receptor interfaces of the simulated receptor/receptor complexes. The MD results are in agreement with the SPR data. Further analyses on the MD results indicated that the ligand binding might increase the hydrogen bonds between the interfaces of the receptor/receptor complex.
authors.affiliation: Drug Discovery and Design Center, State Key Lab of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Graduate School, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Liduo
authors.initials: L
authors.lastname: Yue
authors.forename: Fei
authors.initials: F
authors.lastname: Ye
authors.forename: Chunshan
authors.initials: C
authors.lastname: Gui
authors.forename: Haibin
authors.initials: H
authors.lastname: Luo
authors.forename: Jianhua
authors.initials: J
authors.lastname: Cai
authors.forename: Jianhua
authors.initials: J
authors.lastname: Shen
authors.forename: Kaixian
authors.initials: K
authors.lastname: Chen
authors.forename: Xu
authors.initials: X
authors.lastname: Shen
authors.forename: Hualiang
authors.initials: H
authors.lastname: Jiang
mesh_terms: D004268:DNA-Binding Proteins / Q000378:metabolism*; D019281:Dimerization; D007700:Kinetics; D008024:Ligands; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D047492:Peroxisome Proliferator-Activated Receptors / Q000378:metabolism*; D025941:Protein Interaction Mapping; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D020349:Surface Plasmon Resonance
chemical_list: D004268:DNA-Binding Proteins; D008024:Ligands; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D047492:Peroxisome Proliferator-Activated Receptors; D018160:Receptors, Cytoplasmic and Nuclear
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