3ADS

Human PPARgamma ligand-binding domain in complex with indomethacin

Summary for 3ADS

• Entry DOI: 10.2210/pdb3ads/pdb
• Related: 3ADT 3ADU 3ADV 3ADW 3ADX
• Descriptor: Peroxisome proliferator-activated receptor gamma, INDOMETHACIN (3 entities in total)
• Functional Keywords: nuclear receptor, ligand-dependent transcription factor, ligand-binding domain, activator, diabetes mellitus, disease mutation, dna-binding, metal-binding, nucleus, obesity, phosphoprotein, receptor, transcription, transcription regulation, zinc-finger
• Biological source: Homo sapiens (human)
• Cellular location: Nucleus: P37231
• Total number of polymer chains: 2
• Total formula weight: 66461.01

Authors

Waku, T.,Shiraki, T.,Oyama, T.,Morikawa, K. (deposition date: 2010-01-29, release date: 2010-12-22, Last modification date: 2023-11-01)

Primary citation

Waku, T.,Shiraki, T.,Oyama, T.,Maebara, K.,Nakamori, R.,Morikawa, K.
The nuclear receptor PPARgamma individually responds to serotonin- and fatty acid-metabolites
Embo J., 29:3395-3407, 2010

PubMed Abstract: The nuclear receptor, peroxisome proliferator-activated receptor γ (PPARγ), recognizes various synthetic and endogenous ligands by the ligand-binding domain. Fatty-acid metabolites reportedly activate PPARγ through conformational changes of the Ω loop. Here, we report that serotonin metabolites act as endogenous agonists for PPARγ 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 PPARγ 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 PPARγ-target gene. Collectively, these results suggest a novel agonism, in which PPARγ functions as a multiple sensor in response to distinct metabolites.

PubMed: 20717101
DOI: 10.1038/emboj.2010.197

Experimental method

X-RAY DIFFRACTION (2.25 Å)