title: Molecular dynamics simulation of the ligand binding domain of farnesoid X receptor. Insights into helix-12 stability and coactivator peptide stabilization in response to agonist binding.
abstract: The dynamic changes which take place in the ligand binding domain (LBD) of farneosid X receptor (FXR) in response to agonist binding and in the presence of coactivator peptides were studied with nanosecond time-scale molecular dynamics. Four different systems were analyzed, including the holo-LBD complexed with 6ECDCA, the holo-LBD in the presence of two coactivator peptides, and two artificial apo forms, with and without coactivator peptides. Our results revealed a detailed picture of the differential micro- and macromodifications occurring in the LBD in the presence or not of the agonist molecule and the coactivator peptides. In the apo simulation a major conformational change took place in the crucial helix 12, while the holo-LBD was globally stabilized by the ligand. When the coactivator peptides were included in the simulation, a clear agonist-induced stabilization was observed for the canonical peptide. Interestingly, the second peptide was released from the holo-LBD while it was kept bound in the apo simulation. The present results provide a molecular basis for the understanding the role played by the bile acid agonist in receptor stabilization and enhanced cofactor recruitments.
authors.affiliation: Dipartimento di Chimica e Tecnologia del Farmaco, Università di Perugia, Via del Liceo 1, 06123 Perugia, Italy. gabri@unipg.it
authors.forename: Gabriele
authors.initials: G
authors.lastname: Costantino
authors.forename: Antonio
authors.initials: A
authors.lastname: Entrena-Guadix
authors.forename: Antonio
authors.initials: A
authors.lastname: Macchiarulo
authors.forename: Antimo
authors.initials: A
authors.lastname: Gioiello
authors.forename: Roberto
authors.initials: R
authors.lastname: Pellicciari
mesh_terms: D001665:Binding Sites; D003198:Computer Simulation; D004268:DNA-Binding Proteins / Q000819:agonists* / Q000737:chemistry*; D008024:Ligands; D008958:Models, Molecular; D010455:Peptides / Q000737:chemistry*; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D021281:Quantitative Structure-Activity Relationship; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors / Q000819:agonists* / Q000737:chemistry*; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D004268:DNA-Binding Proteins; D008024:Ligands; D010455:Peptides; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D000099150:Receptor, Farnesoid X-Activated