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Identification of a potent synthetic FXR agonist with an unexpected mode of binding and activation.

Soisson SM, Parthasarathy G, Adams AD, Sahoo S, Sitlani A, Sparrow C, Cui J, Becker JW
Proc Natl Acad Sci U S A 105 5337-42 (2008)
Cited: 52 times
EuropePMC logo PMID: 18391212

Abstract

The farnesoid X receptor (FXR), a member of the nuclear hormone receptor family, plays important roles in the regulation of bile acid and cholesterol homeostasis, glucose metabolism, and insulin sensitivity. There is intense interest in understanding the mechanisms of FXR regulation and in developing pharmaceutically suitable synthetic FXR ligands that might be used to treat metabolic syndrome. We report here the identification of a potent FXR agonist (MFA-1) and the elucidation of the structure of this ligand in ternary complex with the human receptor and a coactivator peptide fragment using x-ray crystallography at 1.9-A resolution. The steroid ring system of MFA-1 binds with its D ring-facing helix 12 (AF-2) in a manner reminiscent of hormone binding to classical steroid hormone receptors and the reverse of the pose adopted by naturally occurring bile acids when bound to FXR. This binding mode appears to be driven by the presence of a carboxylate on MFA-1 that is situated to make a salt-bridge interaction with an arginine residue in the FXR-binding pocket that is normally used to neutralize bound bile acids. Receptor activation by MFA-1 differs from that by bile acids in that it relies on direct interactions between the ligand and residues in helices 11 and 12 and only indirectly involves a protonated histidine that is part of the activation trigger. The structure of the FXR:MFA-1 complex differs significantly from that of the complex with a structurally distinct agonist, fexaramine, highlighting the inherent plasticity of the receptor.

Reviews - 3bej mentioned but not cited (1)

  1. Natural Products Targeting Liver X Receptors or Farnesoid X Receptor. She J, Gu T, Pang X, Liu Y, Tang L, Zhou X. Front Pharmacol 12 772435 (2021)

Articles - 3bej mentioned but not cited (11)

  1. Identification of a potent synthetic FXR agonist with an unexpected mode of binding and activation. Soisson SM, Parthasarathy G, Adams AD, Sahoo S, Sitlani A, Sparrow C, Cui J, Becker JW. Proc. Natl. Acad. Sci. U.S.A. 105 5337-5342 (2008)
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Reviews citing this publication (13)

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  3. Targeting GPR120 and other fatty acid-sensing GPCRs ameliorates insulin resistance and inflammatory diseases. Talukdar S, Olefsky JM, Osborn O. Trends Pharmacol. Sci. 32 543-550 (2011)
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  3. Ligand Binding Mechanism in Steroid Receptors: From Conserved Plasticity to Differential Evolutionary Constraints. Edman K, Hosseini A, Bjursell MK, Aagaard A, Wissler L, Gunnarsson A, Kaminski T, Köhler C, Bäckström S, Jensen TJ, Cavallin A, Karlsson U, Nilsson E, Lecina D, Takahashi R, Grebner C, Geschwindner S, Lepistö M, Hogner AC, Guallar V. Structure 23 2280-2290 (2015)
  4. Investigation of imatinib and other approved drugs as starting points for antidiabetic drug discovery with FXR modulating activity. Steri R, Achenbach J, Steinhilber D, Schubert-Zsilavecz M, Proschak E. Biochem. Pharmacol. 83 1674-1681 (2012)
  5. Structural Basis for Small Molecule NDB (N-Benzyl-N-(3-(tert-butyl)-4-hydroxyphenyl)-2,6-dichloro-4-(dimethylamino) Benzamide) as a Selective Antagonist of Farnesoid X Receptor α (FXRα) in Stabilizing the Homodimerization of the Receptor. Xu X, Xu X, Liu P, Zhu ZY, Chen J, Fu HA, Chen LL, Hu LH, Shen X. J. Biol. Chem. 290 19888-19899 (2015)
  6. Identification of 15d-PGJ2 as an antagonist of farnesoid X receptor: molecular modeling with biological evaluation. Xu X, Lu Y, Chen L, Chen J, Luo X, Shen X. Steroids 78 813-822 (2013)
  7. Alisol B 23-acetate promotes liver regeneration in mice after partial hepatectomy via activating farnesoid X receptor. Meng Q, Chen X, Wang C, Liu Q, Sun H, Sun P, Peng J, Liu K. Biochem. Pharmacol. 92 289-298 (2014)
  8. Discovery of new non-steroidal FXR ligands via a virtual screening workflow based on Phase shape and induced fit docking. Fu J, Si P, Zheng M, Chen L, Shen X, Tang Y, Li W. Bioorg. Med. Chem. Lett. 22 6848-6853 (2012)
  9. 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. Yang L, Broderick D, Jiang Y, Hsu V, Maier CS. Biochim. Biophys. Acta 1844 1684-1693 (2014)
  10. Identification of trisubstituted-pyrazol carboxamide analogs as novel and potent antagonists of farnesoid X receptor. Yu DD, Lin W, Forman BM, Chen T. Bioorg. Med. Chem. 22 2919-2938 (2014)
  11. Letter Discovery of new non-steroidal farnesoid X receptor modulators through 3D shape similarity search and structure-based virtual screening. Wang L, Si P, Sheng Y, Chen Y, Wan P, Shen X, Tang Y, Chen L, Li W. Chem Biol Drug Des 85 481-487 (2015)
  12. Combining self- and cross-docking as benchmark tools: the performance of DockBench in the D3R Grand Challenge 2. Salmaso V, Sturlese M, Cuzzolin A, Moro S. J. Comput. Aided Mol. Des. 32 251-264 (2018)
  13. Design, Synthesis, and Biological Evaluation of Novel Nonsteroidal Farnesoid X Receptor (FXR) Antagonists: Molecular Basis of FXR Antagonism. Huang H, Si P, Wang L, Xu Y, Xu X, Zhu J, Jiang H, Li W, Chen L, Li J. ChemMedChem 10 1184-1199 (2015)
  14. A novel intestinal-restricted FXR agonist. Wang H, Zhao Z, Zhou J, Guo Y, Wang G, Hao H, Xu X. Bioorg. Med. Chem. Lett. 27 3386-3390 (2017)
  15. Computational study of the binding mechanism between farnesoid X receptor α and antagonist N-benzyl-N-(3-(tertbutyl)-4-hydroxyphenyl)-2,6-dichloro-4-(dimethylamino) benzamide. Du J, Qiu M, Guo L, Yao X. J. Biomol. Struct. Dyn. 37 1628-1640 (2019)
  16. Discovery of Natural Products as Novel and Potent FXR Antagonists by Virtual Screening. Diao Y, Jiang J, Zhang S, Li S, Shan L, Huang J, Zhang W, Li H. Front Chem 6 140 (2018)
  17. Lepidozenolide from the liverwort Lepidozia fauriana acts as a farnesoid X receptor agonist. Lin HR. J Asian Nat Prod Res 17 149-158 (2015)
  18. On the relationship of anthranilic derivatives structure and the FXR (Farnesoid X receptor) agonist activity. Kronenberger T, Windshügel B, Wrenger C, Honorio KM, Maltarollo VG. J. Biomol. Struct. Dyn. 36 4378-4391 (2018)
  19. Repurposing FDA-approved drugs as FXR agonists: a structure based in silico pharmacological study. Jose S, Devi SS, Sajeev A, Girisa S, Alqahtani MS, Abbas M, Alshammari A, Sethi G, Kunnumakkara AB. Biosci Rep 43 BSR20212791 (2023)
  20. Using physics-based pose predictions and free energy perturbation calculations to predict binding poses and relative binding affinities for FXR ligands in the D3R Grand Challenge 2. Athanasiou C, Vasilakaki S, Dellis D, Cournia Z. J. Comput. Aided Mol. Des. 32 21-44 (2018)
  21. Conformational Characterization of the Co-Activator Binding Site Revealed the Mechanism to Achieve the Bioactive State of FXR. Kumari A, Mittal L, Srivastava M, Pathak DP, Asthana S. Front Mol Biosci 8 658312 (2021)
  22. Discovery of Farnesoid X Receptor Antagonists Based on a Library of Oleanolic Acid 3-O-Esters through Diverse Substituent Design and Molecular Docking Methods. Wang SR, Xu T, Deng K, Wong CW, Liu J, Fang WS. Molecules 22 (2017)
  23. Discovery of Novel Molecular Frameworks of Farnesoid X Receptor Modulators by Ensemble Machine Learning. Merk D, Grisoni F, Schaller K, Friedrich L, Schneider G. ChemistryOpen 8 7-14 (2019)
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  25. Farnesoid X Receptor Agonists Obeticholic Acid and Chenodeoxycholic Acid Increase Bile Acid Efflux in Sandwich-Cultured Human Hepatocytes: Functional Evidence and Mechanisms. Guo C, LaCerte C, Edwards JE, Brouwer KR, Brouwer KLR. J. Pharmacol. Exp. Ther. 365 413-421 (2018)
  26. Mangrove Tirucallane- and Apotirucallane-Type Triterpenoids: Structure Diversity of the C-17 Side-Chain and Natural Agonists of Human Farnesoid/Pregnane⁻X⁻Receptor. Jiang ZP, Luan ZL, Liu RX, Zhang Q, Ma XC, Shen L, Wu J. Mar Drugs 16 (2018)
  27. Molecular tuning of farnesoid X receptor partial agonism. Merk D, Sreeramulu S, Kudlinzki D, Saxena K, Linhard V, Gande SL, Hiller F, Lamers C, Nilsson E, Aagaard A, Wissler L, Dekker N, Bamberg K, Schubert-Zsilavecz M, Schwalbe H. Nat Commun 10 2915 (2019)


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