title: Is antagonism of E/Z-guggulsterone at the farnesoid X receptor mediated by a noncanonical binding site? A molecular modeling study.
abstract: Guggulsterone 1, the active principle of guggulipid, has been used in ethnic medicine for thousands of years for its antinflammatory and antilipidemic activities. The activities of 1 are apparently mediated by its interaction with an array of nuclear receptors, including endocrine steroid receptors and metabolic lipid receptors. Although relatively weak, the activity at the metabolic farnesoid X receptor (FXR) is particularly intriguing, as 1 is, so far, the only antagonist known for this receptor, with a peculiar ability of gene selective modulation. We report here a systematic study aimed at identifying the potential binding pocket of 1 at FXR. Although 1 could be docked into the canonical binding site, we identified a novel, so far undescribed binding pocket, localized near the loop region between helix 1 and helix 2. This novel binding pocket may explain some of the peculiar characteristics of 1 when acting at FXR.
authors.affiliation: Dipartimento di Chimica e Tecnologia del Farmaco, Università di Perugia, Via del Liceo 1, I-06123 Perugia, Italy.
authors.forename: Udo
authors.initials: U
authors.lastname: Meyer
authors.forename: Gabriele
authors.initials: G
authors.lastname: Costantino
authors.forename: Antonio
authors.initials: A
authors.lastname: Macchiarulo
authors.forename: Roberto
authors.initials: R
authors.lastname: Pellicciari
mesh_terms: D001665:Binding Sites; D029744:Commiphora; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry*; D008024:Ligands; D008958:Models, Molecular; D011282:Pregnenediones / Q000737:chemistry*; D011487:Protein Conformation; D018160:Receptors, Cytoplasmic and Nuclear; D013237:Stereoisomerism; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000737:chemistry*; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D004268:DNA-Binding Proteins; D008024:Ligands; D011282:Pregnenediones; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D000099150:Receptor, Farnesoid X-Activated; C023617:pregna-4,17-diene-3,16-dione