1osh
From Proteopedia
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|PDB= 1osh |SIZE=350|CAPTION= <scene name='initialview01'>1osh</scene>, resolution 1.80Å | |PDB= 1osh |SIZE=350|CAPTION= <scene name='initialview01'>1osh</scene>, resolution 1.80Å | ||
|SITE= | |SITE= | ||
| - | |LIGAND= <scene name='pdbligand=FEX:METHYL 3-{3-[(CYCLOHEXYLCARBONYL){[4'-(DIMETHYLAMINO)BIPHENYL-4-YL]METHYL}AMINO]PHENYL}ACRYLATE'>FEX</scene> | + | |LIGAND= <scene name='pdbligand=FEX:METHYL+3-{3-[(CYCLOHEXYLCARBONYL){[4'-(DIMETHYLAMINO)BIPHENYL-4-YL]METHYL}AMINO]PHENYL}ACRYLATE'>FEX</scene> |
|ACTIVITY= | |ACTIVITY= | ||
|GENE= NR1H4 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens]) | |GENE= NR1H4 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens]) | ||
| + | |DOMAIN= | ||
| + | |RELATEDENTRY= | ||
| + | |RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1osh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1osh OCA], [http://www.ebi.ac.uk/pdbsum/1osh PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=1osh RCSB]</span> | ||
}} | }} | ||
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==Overview== | ==Overview== | ||
The farnesoid X receptor (FXR) functions as a bile acid (BA) sensor coordinating cholesterol metabolism, lipid homeostasis, and absorption of dietary fats and vitamins. However, BAs are poor reagents for characterizing FXR functions due to multiple receptor independent properties. Accordingly, using combinatorial chemistry we evolved a small molecule agonist termed fexaramine with 100-fold increased affinity relative to natural compounds. Gene-profiling experiments conducted in hepatocytes with FXR-specific fexaramine versus the primary BA chenodeoxycholic acid (CDCA) produced remarkably distinct genomic targets. Highly diffracting cocrystals (1.78 A) of fexaramine bound to the ligand binding domain of FXR revealed the agonist sequestered in a 726 A(3) hydrophobic cavity and suggest a mechanistic basis for the initial step in the BA signaling pathway. The discovery of fexaramine will allow us to unravel the FXR genetic network from the BA network and selectively manipulate components of the cholesterol pathway that may be useful in treating cholesterol-related human diseases. | The farnesoid X receptor (FXR) functions as a bile acid (BA) sensor coordinating cholesterol metabolism, lipid homeostasis, and absorption of dietary fats and vitamins. However, BAs are poor reagents for characterizing FXR functions due to multiple receptor independent properties. Accordingly, using combinatorial chemistry we evolved a small molecule agonist termed fexaramine with 100-fold increased affinity relative to natural compounds. Gene-profiling experiments conducted in hepatocytes with FXR-specific fexaramine versus the primary BA chenodeoxycholic acid (CDCA) produced remarkably distinct genomic targets. Highly diffracting cocrystals (1.78 A) of fexaramine bound to the ligand binding domain of FXR revealed the agonist sequestered in a 726 A(3) hydrophobic cavity and suggest a mechanistic basis for the initial step in the BA signaling pathway. The discovery of fexaramine will allow us to unravel the FXR genetic network from the BA network and selectively manipulate components of the cholesterol pathway that may be useful in treating cholesterol-related human diseases. | ||
| - | |||
| - | ==Disease== | ||
| - | Known disease associated with this structure: Breast cancer, susceptibility to OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=601593 601593]] | ||
==About this Structure== | ==About this Structure== | ||
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[[Category: Rosenfeld, J M.]] | [[Category: Rosenfeld, J M.]] | ||
[[Category: Verdecia, M A.]] | [[Category: Verdecia, M A.]] | ||
| - | [[Category: FEX]] | ||
[[Category: ligand binding domain]] | [[Category: ligand binding domain]] | ||
[[Category: nuclear receptor]] | [[Category: nuclear receptor]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun Mar | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun Mar 30 22:49:43 2008'' |
Revision as of 19:49, 30 March 2008
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| , resolution 1.80Å | |||||||
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| Ligands: | |||||||
| Gene: | NR1H4 (Homo sapiens) | ||||||
| Resources: | FirstGlance, OCA, PDBsum, RCSB | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
A Chemical, Genetic, and Structural Analysis of the nuclear bile acid receptor FXR
Overview
The farnesoid X receptor (FXR) functions as a bile acid (BA) sensor coordinating cholesterol metabolism, lipid homeostasis, and absorption of dietary fats and vitamins. However, BAs are poor reagents for characterizing FXR functions due to multiple receptor independent properties. Accordingly, using combinatorial chemistry we evolved a small molecule agonist termed fexaramine with 100-fold increased affinity relative to natural compounds. Gene-profiling experiments conducted in hepatocytes with FXR-specific fexaramine versus the primary BA chenodeoxycholic acid (CDCA) produced remarkably distinct genomic targets. Highly diffracting cocrystals (1.78 A) of fexaramine bound to the ligand binding domain of FXR revealed the agonist sequestered in a 726 A(3) hydrophobic cavity and suggest a mechanistic basis for the initial step in the BA signaling pathway. The discovery of fexaramine will allow us to unravel the FXR genetic network from the BA network and selectively manipulate components of the cholesterol pathway that may be useful in treating cholesterol-related human diseases.
About this Structure
1OSH is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
Reference
A chemical, genetic, and structural analysis of the nuclear bile acid receptor FXR., 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, Mol Cell. 2003 Apr;11(4):1079-92. PMID:12718892
Page seeded by OCA on Sun Mar 30 22:49:43 2008
Categories: Homo sapiens | Single protein | Alvarez, J G.A. | Anisfeld, A M. | Bowman, M E. | Downes, M. | Edwards, P A. | Evans, R M. | Ferrer, J L. | Hogenesch, J B. | Hughes, R. | Kast-Woelbern, H R. | Nicolaou, K C. | Noel, J P. | Roecker, A J. | Rosenfeld, J M. | Verdecia, M A. | Ligand binding domain | Nuclear receptor
