3bej

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[[Image:3bej.jpg|left|200px]]
[[Image:3bej.jpg|left|200px]]
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{{Structure
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<!--
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|PDB= 3bej |SIZE=350|CAPTION= <scene name='initialview01'>3bej</scene>, resolution 1.90&Aring;
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The line below this paragraph, containing "STRUCTURE_3bej", creates the "Structure Box" on the page.
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|SITE= <scene name='pdbsite=AC1:Yt3+Binding+Site+For+Residue+A+1'>AC1</scene>, <scene name='pdbsite=AC2:Yt3+Binding+Site+For+Residue+B+2'>AC2</scene>, <scene name='pdbsite=AC3:Muf+Binding+Site+For+Residue+A+473'>AC3</scene> and <scene name='pdbsite=AC4:Muf+Binding+Site+For+Residue+B+1'>AC4</scene>
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You may change the PDB parameter (which sets the PDB file loaded into the applet)
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|LIGAND= <scene name='pdbligand=MUF:(8ALPHA,10ALPHA,13ALPHA,17BETA)-17-[(4-HYDROXYPHENYL)CARBONYL]ANDROSTA-3,5-DIENE-3-CARBOXYLIC+ACID'>MUF</scene>, <scene name='pdbligand=YT3:YTTRIUM+(III)+ION'>YT3</scene>
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or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
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|ACTIVITY= <span class='plainlinks'>[http://en.wikipedia.org/wiki/Histone_acetyltransferase Histone acetyltransferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.3.1.48 2.3.1.48] </span>
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or leave the SCENE parameter empty for the default display.
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|GENE= NR1H4, BAR, FXR, HRR1, RIP14 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens]), NCOA1, SRC1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])
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-->
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|DOMAIN=
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{{STRUCTURE_3bej| PDB=3bej | SCENE= }}
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|RELATEDENTRY=
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|RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3bej FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3bej OCA], [http://www.ebi.ac.uk/pdbsum/3bej PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=3bej RCSB]</span>
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}}
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'''Structure of human FXR in complex with MFA-1 and co-activator peptide'''
'''Structure of human FXR in complex with MFA-1 and co-activator peptide'''
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==Overview==
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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.
==About this Structure==
==About this Structure==
3BEJ is a [[Protein complex]] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3BEJ OCA].
3BEJ is a [[Protein complex]] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3BEJ OCA].
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==Reference==
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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. 2008 Apr 8;105(14):5337-42. Epub 2008 Apr 7. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/18391212 18391212]
[[Category: Histone acetyltransferase]]
[[Category: Histone acetyltransferase]]
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
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[[Category: Parthasarathy, G]]
[[Category: Parthasarathy, G]]
[[Category: Soisson, S M.]]
[[Category: Soisson, S M.]]
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[[Category: activator]]
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[[Category: Activator]]
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[[Category: acyltransferase]]
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[[Category: Acyltransferase]]
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[[Category: alternative splicing]]
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[[Category: Alternative splicing]]
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[[Category: bar]]
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[[Category: Bar]]
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[[Category: bile acid receptor]]
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[[Category: Bile acid receptor]]
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[[Category: chromosomal rearrangement]]
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[[Category: Chromosomal rearrangement]]
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[[Category: dna-binding]]
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[[Category: Dna-binding]]
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[[Category: fxr]]
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[[Category: Fxr]]
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[[Category: metal-binding]]
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[[Category: Metal-binding]]
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[[Category: nhr]]
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[[Category: Nhr]]
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[[Category: nr1h4]]
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[[Category: Nr1h4]]
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[[Category: nuclear receptor]]
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[[Category: Nuclear receptor]]
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[[Category: nucleus]]
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[[Category: Nucleus]]
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[[Category: phosphoprotein]]
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[[Category: Phosphoprotein]]
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[[Category: polymorphism]]
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[[Category: Polymorphism]]
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[[Category: proto-oncogene]]
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[[Category: Proto-oncogene]]
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[[Category: repressor]]
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[[Category: Repressor]]
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[[Category: transcription]]
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[[Category: Transcription]]
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[[Category: transcription regulation]]
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[[Category: Transcription regulation]]
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[[Category: transcription regulator]]
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[[Category: Transcription regulator]]
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[[Category: transcription/transferase complex]]
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[[Category: Transcription/transferase complex]]
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[[Category: transferase]]
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[[Category: Transferase]]
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[[Category: ubl conjugation]]
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[[Category: Ubl conjugation]]
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[[Category: zinc]]
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[[Category: Zinc]]
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[[Category: zinc-finger]]
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[[Category: Zinc-finger]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Apr 30 13:37:44 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 05:25:34 2008''
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Revision as of 10:37, 30 April 2008

Image:3bej.jpg

Template:STRUCTURE 3bej

Structure of human FXR in complex with MFA-1 and co-activator peptide


Overview

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.

About this Structure

3BEJ is a Protein complex structure of sequences from Homo sapiens. Full crystallographic information is available from OCA.

Reference

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. 2008 Apr 8;105(14):5337-42. Epub 2008 Apr 7. PMID:18391212 Page seeded by OCA on Wed Apr 30 13:37:44 2008

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