6L89

Human PPARgamma ligand binding domain complexed with Butyrolactone 1

6L89 の概要

• エントリーDOI: 10.2210/pdb6l89/pdb
• 分子名称: Peroxisome proliferator-activated receptor gamma, methyl (2R)-3-(4-hydroxyphenyl)-2-[[3-(3-methylbut-2-enyl)-4-oxidanyl-phenyl]methyl]-4-oxidanyl-5-oxidanylidene-furan-2-carboxylate (3 entities in total)
• 機能のキーワード: nuclear receptor ligand binding domain butyrolactone 1 partial agonist, transcription
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 66236.53

構造登録者

Jang, D.M.,Han, B.W. (登録日: 2019-11-05, 公開日: 2020-09-16, 最終更新日: 2023-11-22)

主引用文献

Ahn, S.,Jang, D.M.,Park, S.C.,An, S.,Shin, J.,Han, B.W.,Noh, M.
Cyclin-Dependent Kinase 5 Inhibitor Butyrolactone I Elicits a Partial Agonist Activity of Peroxisome Proliferator-Activated Receptor gamma.
Biomolecules, 10:-, 2020

PubMed Abstract: Adiponectin is an adipocyte-derived cytokine having an insulin-sensitizing activity. During the phenotypic screening of secondary metabolites derived from the marine fungus , a poly cyclin-dependent kinase (CDK) inhibitor butyrolactone I affecting CDK1 and CDK5 was discovered as a potent adiponectin production-enhancing compound in the adipogenesis model of human bone marrow-derived mesenchymal stem cells (hBM-MSCs). CDK5 inhibitors exhibit insulin-sensitizing activities by suppressing the phosphorylation of peroxisome proliferator-activated receptor γ (PPARγ). However, the adiponectin production-enhancing activities of butyrolactone I have not been correlated with the potency of CDK5 inhibitor activities. In a target identification study, butyrolactone I was found to directly bind to PPARγ. In the crystal structure of the human PPARγ, the ligand-binding domain (LBD) in complex with butyrolactone I interacted with the amino acid residues located in the hydrophobic binding pockets of the PPARγ LBD, which is a typical binding mode of the PPARγ partial agonists. Therefore, the adiponectin production-enhancing effect of butyrolactone I was mediated by its polypharmacological dual modulator activities as both a CDK5 inhibitor and a PPARγ partial agonist.

PubMed: 32054125
DOI: 10.3390/biom10020275

実験手法

X-RAY DIFFRACTION (2.1 Å)