1osh
From Proteopedia
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==Overview== | ==Overview== | ||
| - | The farnesoid X receptor (FXR) functions as a bile acid (BA) sensor | + | 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== | ==Disease== | ||
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[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
| - | [[Category: Alvarez, J | + | [[Category: Alvarez, J G.A.]] |
| - | [[Category: Anisfeld, A | + | [[Category: Anisfeld, A M.]] |
| - | [[Category: Bowman, M | + | [[Category: Bowman, M E.]] |
[[Category: Downes, M.]] | [[Category: Downes, M.]] | ||
| - | [[Category: Edwards, P | + | [[Category: Edwards, P A.]] |
| - | [[Category: Evans, R | + | [[Category: Evans, R M.]] |
| - | [[Category: Ferrer, J | + | [[Category: Ferrer, J L.]] |
| - | [[Category: Hogenesch, J | + | [[Category: Hogenesch, J B.]] |
[[Category: Hughes, R.]] | [[Category: Hughes, R.]] | ||
| - | [[Category: Kast-Woelbern, H | + | [[Category: Kast-Woelbern, H R.]] |
| - | [[Category: Nicolaou, K | + | [[Category: Nicolaou, K C.]] |
| - | [[Category: Noel, J | + | [[Category: Noel, J P.]] |
| - | [[Category: Roecker, A | + | [[Category: Roecker, A J.]] |
| - | [[Category: Rosenfeld, J | + | [[Category: Rosenfeld, J M.]] |
| - | [[Category: Verdecia, M | + | [[Category: Verdecia, M A.]] |
[[Category: FEX]] | [[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 | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 14:21:08 2008'' |
Revision as of 12:21, 21 February 2008
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A Chemical, Genetic, and Structural Analysis of the nuclear bile acid receptor FXR
Contents |
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.
Disease
Known disease associated with this structure: Breast cancer, susceptibility to OMIM:[601593]
About this Structure
1OSH is a Single protein structure of sequence from Homo sapiens with as ligand. 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 Thu Feb 21 14:21:08 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. | FEX | Ligand binding domain | Nuclear receptor
