7AWD

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

7AWD の概要

• エントリーDOI: 10.2210/pdb7awd/pdb
• 分子名称: Peroxisome proliferator-activated receptor gamma, (2Z,6E,10E)-13-[(2R)-6-hydroxy-2,8-dimethyl-3,4-dihydro-2H-1-benzopyran-2-yl]-2,6,10-trimethyltrideca-2,6,10-trienoic acid, CITRIC ACID, ... (5 entities in total)
• 機能のキーワード: pparg, steroid hormone receptor, garcinoic acid, structural genomics consortium, sgc, dna binding protein
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 32989.38

構造登録者

Chaikuad, A.,Merk, D.,Knapp, S.,Structural Genomics Consortium (SGC) (登録日: 2020-11-06, 公開日: 2020-11-25, 最終更新日: 2024-01-31)

主引用文献

Willems, S.,Gellrich, L.,Chaikuad, A.,Kluge, S.,Werz, O.,Heering, J.,Knapp, S.,Lorkowski, S.,Schubert-Zsilavecz, M.,Merk, D.
Endogenous vitamin E metabolites mediate allosteric PPAR gamma activation with unprecedented co-regulatory interactions.
Cell Chem Biol, 28:1489-1500.e8, 2021

PubMed Abstract: Vitamin E exhibits pharmacological effects beyond established antioxidant activity suggesting involvement of unidentified mechanisms. Here, we characterize endogenously formed tocopherol carboxylates and the vitamin E mimetic garcinoic acid (GA) as activators of the peroxisome proliferator-activated receptor gamma (PPARγ). Co-stimulation of PPARγ with GA and the orthosteric agonist pioglitazone resulted in additive transcriptional activity. In line with this, the PPARγ-GA complex adopted a fully active conformation and interestingly contained two bound GA molecules with one at an allosteric site. A co-regulator interaction scan demonstrated an unanticipated co-factor recruitment profile for GA-bound PPARγ compared with canonical PPARγ agonists and gene expression analysis revealed different effects of GA and pioglitazone on PPAR signaling in hepatocytes. These observations reveal allosteric mechanisms of PPARγ modulation as an alternative avenue to PPARγ targeting and suggest contributions of PPARγ activation by α-13-tocopherolcarboxylate to the pharmacological effects of vitamin E.

PubMed: 33989565
DOI: 10.1016/j.chembiol.2021.04.019

実験手法

X-RAY DIFFRACTION (1.93 Å)