دورية أكاديمية
Mechanistic Impact of Different Ligand Scaffolds on FXR Modulation Suggests Avenues to Selective Modulators.
| العنوان: | Mechanistic Impact of Different Ligand Scaffolds on FXR Modulation Suggests Avenues to Selective Modulators. |
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| المؤلفون: | Heering J; Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, and Fraunhofer Cluster of Excellence for Immune Mediated Diseases CIMD, 60596Frankfurt, Germany., Jores N; Institute for Organic Chemistry and Chemical Biology, Center for Biomolecular Magnetic Resonance (BMRZ), Goethe-University Frankfurt, 60438Frankfurt, Germany., Kilu W; Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, 60438Frankfurt, Germany., Schallmayer E; Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, 60438Frankfurt, Germany., Peelen E; Immunic AG, 82166Gräfelfing, Germany., Muehler A; Immunic AG, 82166Gräfelfing, Germany., Kohlhof H; Immunic AG, 82166Gräfelfing, Germany., Vitt D; Immunic AG, 82166Gräfelfing, Germany., Linhard V; Institute for Organic Chemistry and Chemical Biology, Center for Biomolecular Magnetic Resonance (BMRZ), Goethe-University Frankfurt, 60438Frankfurt, Germany., Gande SL; Institute for Organic Chemistry and Chemical Biology, Center for Biomolecular Magnetic Resonance (BMRZ), Goethe-University Frankfurt, 60438Frankfurt, Germany., Chaikuad A; Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, 60438Frankfurt, Germany., Sreeramulu S; Institute for Organic Chemistry and Chemical Biology, Center for Biomolecular Magnetic Resonance (BMRZ), Goethe-University Frankfurt, 60438Frankfurt, Germany., Schwalbe H; Institute for Organic Chemistry and Chemical Biology, Center for Biomolecular Magnetic Resonance (BMRZ), Goethe-University Frankfurt, 60438Frankfurt, Germany., Merk D; Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, 60438Frankfurt, Germany.; Department of Pharmacy, Ludwig-Maximilians-Universität München, 81377Munich, Germany. |
| المصدر: | ACS chemical biology [ACS Chem Biol] 2022 Nov 18; Vol. 17 (11), pp. 3159-3168. Date of Electronic Publication: 2022 Nov 01. |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Chemical Society Country of Publication: United States NLM ID: 101282906 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1554-8937 (Electronic) Linking ISSN: 15548929 NLM ISO Abbreviation: ACS Chem Biol Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Washington, D.C. : American Chemical Society, c2006- |
| مواضيع طبية MeSH: | Receptors, Cytoplasmic and Nuclear* , Bile Acids and Salts*, Ligands ; Protein Domains ; Cell Nucleus |
| مستخلص: | The bile-acid sensing nuclear farnesoid X receptor (FXR) is an attractive target for the treatment of hepatic and metabolic diseases, but application of this chemotherapeutic concept remains limited due to adverse effects of FXR activation observed in clinical trials. To elucidate the mechanistic basis of FXR activation at the molecular level, we have systematically studied FXR co-regulator interactions and dimerization in response to seven chemically diverse FXR ligands. Different molecular effects on FXR activation mediated by different scaffolds were evident and aligned with characteristic structural changes within the ligand binding domain of FXR. A partial FXR agonist acted mainly through co-repressor displacement from FXR and caused an FXR-regulated gene expression pattern markedly differing from FXR agonist effects. These results suggest selective modulation of FXR dimerization and co-regulator interactions for different ligands, offering a potential avenue for the design of gene- or tissue-selective FXR modulators. |
| المشرفين على المادة: | 0 (Ligands) 0 (Receptors, Cytoplasmic and Nuclear) 0 (Bile Acids and Salts) |
| تواريخ الأحداث: | Date Created: 20221101 Date Completed: 20221121 Latest Revision: 20230119 |
| رمز التحديث: | 20230120 |
| DOI: | 10.1021/acschembio.2c00599 |
| PMID: | 36318238 |
| قاعدة البيانات: | MEDLINE |
Find this issue from the American Chemical Society | تدمد: | 1554-8937 |
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| DOI: | 10.1021/acschembio.2c00599 |