3L1B
Complex Structure of FXR Ligand-binding domain with a tetrahydroazepinoindole compound
Summary for 3L1B
| Entry DOI | 10.2210/pdb3l1b/pdb |
| Related | 1OSH |
| Descriptor | Farnesoid X receptor, 1-methylethyl 8-fluoro-1,1-dimethyl-3-{[4-(3-morpholin-4-ylpropoxy)phenyl]carbonyl}-1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxylate (3 entities in total) |
| Functional Keywords | nuclear receptor, fxr agonist, fxr ligand-binding domain, nucleus, receptor, transcription regulation, transcription |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 27705.78 |
| Authors | Xu, W.,Lundquist, J.T. (deposition date: 2009-12-11, release date: 2010-03-02, Last modification date: 2024-04-03) |
| Primary citation | Lundquist, J.T.,Harnish, D.C.,Kim, C.Y.,Mehlmann, J.F.,Unwalla, R.J.,Phipps, K.M.,Crawley, M.L.,Commons, T.,Green, D.M.,Xu, W.,Hum, W.T.,Eta, J.E.,Feingold, I.,Patel, V.,Evans, M.J.,Lai, K.,Borges-Marcucci, L.,Mahaney, P.E.,Wrobel, J.E. Improvement of Physiochemical Properties of the Tetrahydroazepinoindole Series of Farnesoid X Receptor (FXR) Agonists: Beneficial Modulation of Lipids in Primates. J.Med.Chem., 53:1774-1787, 2010 Cited by PubMed Abstract: In an effort to develop orally active farnesoid X receptor (FXR) agonists, a series of tetrahydroazepinoindoles with appended solubilizing amine functionalities were synthesized. The crystal structure of the previously disclosed FXR agonist, 1 (FXR-450), aided in the design of compounds with tethered solubilizing functionalities designed to reach the solvent cavity around the hFXR receptor. These compounds were soluble in 0.5% methylcellulose/2% Tween-80 in water (MC/T) for oral administration. In vitro and in vivo optimization led to the identification of 14dd and 14cc, which in a dose-dependent fashion regulated low density lipoprotein cholesterol (LDLc) in low density lipoprotein receptor knockout (LDLR(-/-)) mice. Compound 14cc was dosed in female rhesus monkeys for 4 weeks at 60 mg/kg daily in MC/T vehicle. After 7 days, triglyceride (TG) levels and very low density lipoprotein cholesterol (VLDLc) levels were significantly decreased and LDLc was decreased 63%. These data are the first to demonstrate the dramatic lowering of serum LDLc levels by a FXR agonist in primates and supports the potential utility of 14cc in treating dyslipidemia in humans beyond just TG lowering. PubMed: 20095622DOI: 10.1021/jm901650u PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.9 Å) |
Structure validation
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