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3fli

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Discovery of XL335, a Highly Potent, Selective and Orally-Active Agonist of the Farnesoid X Receptor (FXR)

Structural highlights

3fli is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

NR1H4_HUMAN Ligand-activated transcription factor. Receptor for bile acids such as chenodeoxycholic acid, lithocholic acid and deoxycholic acid. Represses the transcription of the cholesterol 7-alpha-hydroxylase gene (CYP7A1) through the induction of NR0B2 or FGF19 expression, via two distinct mechanisms. Activates the intestinal bile acid-binding protein (IBABP). Activates the transcription of bile salt export pump ABCB11 by directly recruiting histone methyltransferase CARM1 to this locus.^[1] ^[2] ^[3] ^[4] ^[5] ^[6] ^[7] ^[8]

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

References

↑ Makishima M, Okamoto AY, Repa JJ, Tu H, Learned RM, Luk A, Hull MV, Lustig KD, Mangelsdorf DJ, Shan B. Identification of a nuclear receptor for bile acids. Science. 1999 May 21;284(5418):1362-5. PMID:10334992
↑ Parks DJ, Blanchard SG, Bledsoe RK, Chandra G, Consler TG, Kliewer SA, Stimmel JB, Willson TM, Zavacki AM, Moore DD, Lehmann JM. Bile acids: natural ligands for an orphan nuclear receptor. Science. 1999 May 21;284(5418):1365-8. PMID:10334993
↑ Holt JA, Luo G, Billin AN, Bisi J, McNeill YY, Kozarsky KF, Donahee M, Wang DY, Mansfield TA, Kliewer SA, Goodwin B, Jones SA. Definition of a novel growth factor-dependent signal cascade for the suppression of bile acid biosynthesis. Genes Dev. 2003 Jul 1;17(13):1581-91. Epub 2003 Jun 18. PMID:12815072 doi:10.1101/gad.1083503
↑ Ananthanarayanan M, Li S, Balasubramaniyan N, Suchy FJ, Walsh MJ. Ligand-dependent activation of the farnesoid X-receptor directs arginine methylation of histone H3 by CARM1. J Biol Chem. 2004 Dec 24;279(52):54348-57. Epub 2004 Oct 6. PMID:15471871 doi:M410021200
↑ Downes M, Verdecia MA, Roecker AJ, Hughes R, Hogenesch JB, Kast-Woelbern HR, Bowman ME, Ferrer JL, Anisfeld AM, Edwards PA, Rosenfeld JM, Alvarez JG, Noel JP, Nicolaou KC, Evans RM. A chemical, genetic, and structural analysis of the nuclear bile acid receptor FXR. Mol Cell. 2003 Apr;11(4):1079-92. PMID:12718892
↑ Akwabi-Ameyaw A, Bass JY, Caldwell RD, Caravella JA, Chen L, Creech KL, Deaton DN, Jones SA, Kaldor I, Liu Y, Madauss KP, Marr HB, McFadyen RB, Miller AB, Iii FN, Parks DJ, Spearing PK, Todd D, Williams SP, Wisely GB. Conformationally constrained farnesoid X receptor (FXR) agonists: Naphthoic acid-based analogs of GW 4064. Bioorg Med Chem Lett. 2008 Aug 1;18(15):4339-43. Epub 2008 Jun 28. PMID:18621523 doi:10.1016/j.bmcl.2008.06.073
↑ Bass JY, Caldwell RD, Caravella JA, Chen L, Creech KL, Deaton DN, Madauss KP, Marr HB, McFadyen RB, Miller AB, Parks DJ, Todd D, Williams SP, Wisely GB. Substituted isoxazole analogs of farnesoid X receptor (FXR) agonist GW4064. Bioorg Med Chem Lett. 2009 Jun 1;19(11):2969-73. Epub 2009 Apr 18. PMID:19410460 doi:10.1016/j.bmcl.2009.04.047
↑ Akwabi-Ameyaw A, Bass JY, Caldwell RD, Caravella JA, Chen L, Creech KL, Deaton DN, Madauss KP, Marr HB, McFadyen RB, Miller AB, Navas F 3rd, Parks DJ, Spearing PK, Todd D, Williams SP, Bruce Wisely G. FXR agonist activity of conformationally constrained analogs of GW 4064. Bioorg Med Chem Lett. 2009 Aug 15;19(16):4733-9. Epub 2009 Jun 21. PMID:19586769 doi:10.1016/j.bmcl.2009.06.062