2ZK6: Human Peroxisome Proliferator-Activated Receptor Gamma Ligand Binding Domain Complexed With C8-Bodipy

Citation:
Abstract
The nuclear receptor, peroxisome proliferator-activated receptor gamma (PPARgamma), recognizes various synthetic and endogenous ligands by the ligand-binding domain. Fatty-acid metabolites reportedly activate PPARgamma through conformational changes of the Omega loop. Here, we report that serotonin metabolites act as endogenous agonists for PPARgamma to regulate macrophage function and adipogenesis by directly binding to helix H12. A cyclooxygenase inhibitor, indomethacin, is a mimetic agonist of these metabolites. Crystallographic analyses revealed that an indole acetate functions as a common moiety for the recognition by the sub-pocket near helix H12. Intriguingly, a serotonin metabolite and a fatty-acid metabolite each bind to distinct sub-pockets, and the PPARgamma antagonist, T0070907, blocked the fatty-acid agonism, but not that of the serotonin metabolites. Mutational analyses on receptor-mediated transcription and coactivator binding revealed that each metabolite individually uses coregulator and/or heterodimer interfaces in a ligand-type-specific manner. Furthermore, the inhibition of the serotonin metabolism reduced the expression of the endogenous PPARgamma-target gene. Collectively, these results suggest a novel agonism, in which PPARgamma functions as a multiple sensor in response to distinct metabolites.
PDB ID: 2ZK6Download
MMDB ID: 69794
PDB Deposition Date: 2008/3/12
Updated in MMDB: 2010/12
Experimental Method:
x-ray diffraction
Resolution: 2.41  Å
Source Organism:
Similar Structures:
Biological Unit for 2ZK6: dimeric; determined by author
Molecular Components in 2ZK6
Label Count Molecule
Proteins (2 molecules)
2
Peroxisome Proliferator-activated Receptor Gamma(Gene symbol: PPARG)
Molecule annotation
Chemicals (2 molecules)
1
2
* Click molecule labels to explore molecular sequence information.

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