title: Binding analyses between Human PPARgamma-LBD and ligands.
abstract: The binding characteristics of a series of PPARgamma ligands (GW9662, GI 262570, cis-parinaric acid, 15-deoxy-Delta(12,14)-prostaglandin J(2), LY171883, indomethacin, linoleic acid, palmitic acid and troglitazone) to human PPARgamma ligand binding domain have been investigated for the first time by using surface plasmon resonance biosensor technology, CD spectroscopy and molecular docking simulation. The surface plasmon resonance biosensor determined equilibrium dissociation constants (KD values) are in agreement with the results reported in the literature measured by other methods, indicating that the surface plasmon resonance biosensor can assume a direct assay method in screening new PPARgamma agonists or antagonists. Conformational changes of PPARgamma caused by the ligand binding were detected by CD determination. It is interesting that the thermal stability of the receptor, reflected by the increase of the transition temperature (T(m)), was enhanced by the binding of the ligands. The increment of the transition temperature (DeltaT(m)) of PPARgamma owing to ligand binding correlated well with the binding affinity. This finding implies that CD could possibly be a complementary technology with which to determine the binding affinities of ligands to PPARgamma. Molecular docking simulation provided reasonable and reliable binding models of the ligands to PPARgamma at the atomic level, which gave a good explanation of the structure-binding affinity relationship for the ligands interacting with PPARgamma. Moreover, the predicted binding free energies for the ligands correlated well with the binding constants measured by the surface plasmon resonance biosensor, indicating that the docking paradigm used in this study could possibly be employed in virtual screening to discover new PPARgamma ligands, although the docking program cannot accurately predict the absolute ligand-PPARgamma binding affinity.
authors.affiliation: Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Changying
authors.initials: C
authors.lastname: Yu
authors.forename: Lili
authors.initials: L
authors.lastname: Chen
authors.forename: Haibing
authors.initials: H
authors.lastname: Luo
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.forename: Feng
authors.initials: F
authors.lastname: Cheng
authors.forename: Chunshan
authors.initials: C
authors.lastname: Gui
authors.forename: Ruihao
authors.initials: R
authors.lastname: Zhang
authors.forename: Jianhua
authors.initials: J
authors.lastname: Shen
authors.forename: Kaixian
authors.initials: K
authors.lastname: Chen
authors.forename: Hualiang
authors.initials: H
authors.lastname: Jiang
authors.forename: Xu
authors.initials: X
authors.lastname: Shen
mesh_terms: D001059:Apoproteins / Q000737:chemistry*; D001665:Binding Sites; D002942:Circular Dichroism; D003198:Computer Simulation; D006801:Humans; D008024:Ligands; D050356:Lipid Metabolism; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D011994:Recombinant Proteins; D020349:Surface Plasmon Resonance; D013696:Temperature; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D001059:Apoproteins; D008024:Ligands; D018160:Receptors, Cytoplasmic and Nuclear; D011994:Recombinant Proteins; D014157:Transcription Factors