1osh

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Revision as of 16:29, 12 November 2007

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spinqualitylabelsall models 1osh, resolution 1.80Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

A Chemical, Genetic, and Structural Analysis of the nuclear bile acid receptor FXR

Contents 1 Overview 2 Disease 3 About this Structure 4 Reference

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 FEX 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

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