6TSG

Crystal structure of Peroxisome proliferator-activated receptor gamma (PPARG) in complex with TETRAC

Summary for 6TSG

• Entry DOI: 10.2210/pdb6tsg/pdb
• Descriptor: Peroxisome proliferator-activated receptor gamma, 3,3',5,5'-TETRAIODOTHYROACETIC ACID (3 entities in total)
• Functional Keywords: pparg, steroid hormone receptor, inhibitor, structural genomics, structural genomics consortium, sgc, dna binding protein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 32415.62

Authors

Chaikuad, A.,Gellrich, L.,Arrowsmith, C.H.,Edwards, A.M.,Bountra, C.,Merk, D.,Knapp, S.,Structural Genomics Consortium (SGC) (deposition date: 2019-12-20, release date: 2020-07-22, Last modification date: 2024-01-24)

Primary citation

Gellrich, L.,Heitel, P.,Heering, J.,Kilu, W.,Pollinger, J.,Goebel, T.,Kahnt, A.,Arifi, S.,Pogoda, W.,Paulke, A.,Steinhilber, D.,Proschak, E.,Wurglics, M.,Schubert-Zsilavecz, M.,Chaikuad, A.,Knapp, S.,Bischoff, I.,Furst, R.,Merk, D.
l-Thyroxin and the Nonclassical Thyroid Hormone TETRAC Are Potent Activators of PPAR gamma.
J.Med.Chem., 63:6727-6740, 2020

PubMed Abstract: Thyroid hormones (THs) operate numerous physiological processes through modulation of the nuclear thyroid hormone receptors and several other proteins. We report direct activation of the nuclear peroxisome proliferator-activated receptor gamma (PPARγ) and retinoid X receptor (RXR) by classical and nonclassical THs as another molecular activity of THs. The T4 metabolite TETRAC was the most active TH on PPARγ with nanomolar potency and binding affinity. We demonstrate that TETRAC promotes PPARγ/RXR signaling in cell-free, cellular, and settings. Simultaneous activation of the heterodimer partners PPARγ and RXR resulted in high dimer activation efficacy. Compared to fatty acids as known natural ligands of PPARγ and RXR, TETRAC differs markedly in its molecular structure and the PPARγ-TETRAC complex revealed a distinctive binding mode of the TH. Our observations suggest a potential connection of TH and PPAR signaling through overlapping ligand recognition and may hold implications for TH and PPAR pharmacology.

PubMed: 32356658
DOI: 10.1021/acs.jmedchem.9b02150

Experimental method

X-RAY DIFFRACTION (2.98 Å)