Article

Effect of heterodimer partner RXRα on PPARγ activation function-2 helix in solution

Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO 63110, USA
Biochemical and Biophysical Research Communications DOI:10.1016/j.bbrc.2007.10.143 pp.42-46

ABSTRACT The structural mechanism of allosteric communication between retinoid X receptor (RXR) and its heterodimer partners remains controversial. As a first step towards addressing this question, we report a nuclear magnetic resonance (NMR) study on the GW1929-bound peroxisome proliferator-activated receptor gamma (PPARγ) ligand-binding domain (LBD) with and without the 9-cis-retinoic acid (9cRA)-bound RXRα LBD. Sequence-specific 13Cα, 13Cβ, and 13CO resonance assignments have been established for over 95% of the 275 residues in the PPARγ LBD monomer. The 1HN, 15N, and 13CO chemical shift perturbations induced by the RXRα LBD binding are located at not only the heterodimer interface that includes the C-terminal residue Y477 but also residues Y473 and K474 in the activation function-2 (AF-2) helix. This result suggests that 9cRA-bound RXRα can affect the PPARγ AF-2 helix in solution and demonstrates that NMR is a powerful new tool for studying the mechanism of allosteric ligand activation in RXR heterodimers.

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Keywords

13CO chemical shift perturbations induced
 
13CO resonance assignments
 
9-cis-retinoic acid
 
9cRA)-bound RXRα LBD
 
9cRA-bound RXRα
 
activation function-2
 
allosteric communication
 
C-terminal residue Y477
 
first step
 
GW1929-bound peroxisome proliferator-activated receptor gamma
 
heterodimer interface
 
heterodimer partners
 
nuclear magnetic resonance
 
powerful new tool
 
retinoid X receptor
 
RXRα LBD binding
 
Sequence-specific 13Cα
 

Jianyun Lu