Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:B6ZGS9 (Farnesoid X receptor)
 212 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The Farnesoid X receptor (FXR) has recently become a potential therapeutical target. The recruitment of coactivator protein (specified by LXXLL sequence) is the initial step in transcriptional activation of nuclear receptors (NRs). In this paper, the process of recognition of the LXXLL motif by the ligand binding domain (LBD) of FXR is observed in a 25 ns molecular dynamics simulation. The hydrophobic and hydrogen bonding interactions between the LBD and the coactivator are fully analyzed. This observation provides justification for the 'on deck' model proposed by Nettles and Greene. At last, insight to the protein-polypeptide interactions and protein conformational changes are discussed.
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PMID:Recognition of LXXLL by ligand binding domain of the Farnesoid X receptor in molecular dynamics simulation. 1712 2

Farnesoid X receptor (FXR) is a member of the nuclear receptor superfamily of transcription factors that plays a key role in the regulation of bile acids, lipid and glucose metabolisms. The regulative function of FXR is governed by conformational changes of the ligand binding domain (LBD) upon ligand binding. Although FXR is a highly researched potential therapeutic target, only a limited number of FXR-agonist complexes have been successfully crystallized and subsequently yielded high resolution structures. There is currently no structural information of any FXR-antagonist complexes publically available. We therefore explored the use of amide hydrogen/deuterium exchange (HDX) coupled with mass spectrometry for characterizing conformational changes in the FXR-LBD upon ligand binding. Ligand-specific deuterium incorporation profiles were obtained for three FXR ligand chemotypes: GW4064, a synthetic non-steroidal high affinity agonist; the bile acid chenodeoxycholic acid (CDCA), the endogenous low affinity agonist of FXR; and Z-guggulsterone (GG), an in vitro antagonist of the steroid chemotype. A comparison of the HDX profiles of their ligand-bound FXR-LBD complexes revealed a unique mode of interaction for GG. The conformational features of the FXR-LBD-antagonist interaction are discussed.
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PMID:Conformational dynamics of human FXR-LBD ligand interactions studied by hydrogen/deuterium exchange mass spectrometry: insights into the antagonism of the hypolipidemic agent Z-guggulsterone. 2495 69

Farnesoid X receptor (FXR) agonists can reverse dysregulated bile acid metabolism, and thus, they are potential therapeutics to prevent and treat nonalcoholic fatty liver disease. The low success rate of FXR agonists' R&D and the side effects of clinical candidates such as obeticholic acid make it urgent to discover new chemotypes. Unfortunately, structure-based virtual screening (SBVS) that can speed up drug discovery has rarely been reported with success for FXR, which was likely hindered by the failure in addressing protein flexibility. To address this issue, we devised human FXR (hFXR)-specific ensemble learning models based on pose filters from 24 agonist-bound hFXR crystal structures and coupled them to traditional SBVS approaches of the FRED docking plus Chemgauss4 scoring function. It turned out that the hFXR-specific pose filter ensemble (PFE) was able to improve ligand enrichment significantly, which rendered 3RUT-based SBVS with its PFE the ideal approach for FXR agonist discovery. By screening of the Specs chemical library and in vitro FXR transactivation bioassay, we identified a new class of FXR agonists with compound XJ034 as the representative, which would have been missed if the PFE was not coupled. Following that, we performed in-depth biological studies which demonstrated that XJ034 resulted in a downtrend of intracellular triglyceride in vitro, significantly decreased the serum/liver TG in high fat diet-induced C57BL/6J obese mice, and more importantly, showed metabolic stabilities in both plasma and liver microsomes. To provide insight into further structure-based lead optimization, we solved the crystal structure of hFXR complexed with compound XJ034, uncovering a unique hydrogen bond between compound XJ034 and residue Y375. The current work highlights the power of our pose filter-based ensemble learning approach in terms of scaffold hopping and provides a promising lead compound for further development.
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PMID:Pose Filter-Based Ensemble Learning Enables Discovery of Orally Active, Nonsteroidal Farnesoid X Receptor Agonists. 3205 66