5wzx

From Proteopedia

(Difference between revisions)

Revision as of 08:18, 17 January 2018

Structural basis for a pentacyclic oleanane-type triterpenoid as a ligand of FXR

Structural highlights

5wzx is a 4 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	,
Gene:	NR1H4, BAR, FXR, HRR1, RIP14 (HUMAN)
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

[NCOA2_HUMAN] Note=Chromosomal aberrations involving NCOA2 may be a cause of acute myeloid leukemias. Inversion inv(8)(p11;q13) generates the KAT6A-NCOA2 oncogene, which consists of the N-terminal part of KAT6A and the C-terminal part of NCOA2/TIF2. KAT6A-NCOA2 binds to CREBBP and disrupts its function in transcription activation.

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] [NCOA2_HUMAN] Transcriptional coactivator for steroid receptors and nuclear receptors. Coactivator of the steroid binding domain (AF-2) but not of the modulating N-terminal domain (AF-1). Required with NCOA1 to control energy balance between white and brown adipose tissues.^[9]

Publication Abstract from PubMed

Farnesoid X receptor (FXR) and G-protein-coupled bile acid receptor 1 (GPBAR1) are two important bile acid (BA) receptors. As non-BAs drug template for GPBAR1, none of the natural oleanane-type triterpenes have been reported as FXR ligands, despite FXR and GPBAR1 having similar binding pockets for BAs. Here, we report the natural triterpene hedragonic acid that has been isolated from the stem and root of Celastrus orbiculatus Thunb. (COT) as an effective agonist for FXR. Both biochemical amplified luminescent proximity homogeneous assay and cell-based reporter assays showed that hedragonic acid regulated the transcriptional activity of FXR. Circular dichroism spectroscopy further suggested the conformational changes of FXR upon the binding of hedragonic acid. Interestingly, the crystal structure of hedragonic acid-bound FXR revealed a unique binding mode with hedragonic acid occupying a novel binding pocket different from the classic binding position. The structural comparison between hedragonic acid-bound FXR and oleanolic acid-bound GPBAR1 explained the molecular basis for the selectivity of oleanane-type triterpenes for FXR. Moreover, hedragonic acid treatment protected mice from liver injury induced by acetaminophen overdose and decreased hepatic inflammatory responses in an FXR-dependent manner, suggesting that hedragonic acid might be one of the major components of COT for its multifunctional pharmaceutical uses. In conclusion, our results provide novel structure templates for drug design based on natural triterpenes by targeting FXR and/or GPBAR1 with pharmaceutical values.

Identification of an Oleanane-Type Triterpene Hedragonic Acid as a Novel Farnesoid X Receptor Ligand with Liver Protective Effects and Anti-inflammatory Activity.,Lu Y, Zheng W, Lin S, Guo F, Zhu Y, Wei Y, Liu X, Jin S, Jin L, Li Y Mol Pharmacol. 2018 Feb;93(2):63-72. doi: 10.1124/mol.117.109900. Epub 2017 Nov, 21. PMID:29162643^[10]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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
↑ Voegel JJ, Heine MJ, Tini M, Vivat V, Chambon P, Gronemeyer H. The coactivator TIF2 contains three nuclear receptor-binding motifs and mediates transactivation through CBP binding-dependent and -independent pathways. EMBO J. 1998 Jan 15;17(2):507-19. PMID:9430642 doi:10.1093/emboj/17.2.507
↑ Lu Y, Zheng W, Lin S, Guo F, Zhu Y, Wei Y, Liu X, Jin S, Jin L, Li Y. Identification of an Oleanane-Type Triterpene Hedragonic Acid as a Novel Farnesoid X Receptor Ligand with Liver Protective Effects and Anti-inflammatory Activity. Mol Pharmacol. 2018 Feb;93(2):63-72. doi: 10.1124/mol.117.109900. Epub 2017 Nov, 21. PMID:29162643 doi:http://dx.doi.org/10.1124/mol.117.109900

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/5wzx"

Categories: Human | Li, Y | Lu, Y | Fxr ligand | Transcription

@@ Line 3: / Line 3: @@
 <StructureSection load='5wzx' size='340' side='right' caption='[[5wzx]], [[Resolution|resolution]] 2.95&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5wzx]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5WZX OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5WZX FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5wzx]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5WZX OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5WZX FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=7VX:(4aR,6aR,6aS,6bS,8aS,9R,12aR,14bR)-2,2,6a,6b,9,12a-hexamethyl-10-oxidanylidene-1,3,4,5,6,6a,7,8,8a,9,11,12,13,14b-tetradecahydropicene-4a-carboxylic+acid'>7VX</scene>, <scene name='pdbligand=BU3:(R,R)-2,3-BUTANEDIOL'>BU3</scene></td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">NR1H4, BAR, FXR, HRR1, RIP14 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
 <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5wzx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5wzx OCA], [http://pdbe.org/5wzx PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5wzx RCSB], [http://www.ebi.ac.uk/pdbsum/5wzx PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5wzx ProSAT]</span></td></tr>
 </table>
@@ Line 24: / Line 25: @@
 __TOC__
 </StructureSection>
+[[Category: Human]]
 [[Category: Li, Y]]
 [[Category: Lu, Y]]
 [[Category: Fxr ligand]]
 [[Category: Transcription]]

5wzx

From Proteopedia

Revision as of 08:18, 17 January 2018

Structural basis for a pentacyclic oleanane-type triterpenoid as a ligand of FXR

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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