8BF2

Human PPARgamma in complex with MEHP bound to the AF-2 and omega sub-pockets

Summary for 8BF2

• Entry DOI: 10.2210/pdb8bf2/pdb
• Descriptor: Peroxisome proliferator-activated receptor gamma, 2-[(2~{S})-2-ethylhexoxy]carbonylbenzoic acid (3 entities in total)
• Functional Keywords: ppar gamma activation, ligand binding domain, mehp, environmental contaminant, nuclear protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 65660.18

Authors

Useini, A.,Straeter, N. (deposition date: 2022-10-23, release date: 2023-03-08, Last modification date: 2024-02-07)

Primary citation

Useini, A.,Engelberger, F.,Kunze, G.,Strater, N.
Structural basis of the activation of PPAR gamma by the plasticizer metabolites MEHP and MINCH.
Environ Int, 173:107822-107822, 2023

PubMed Abstract: Di-2-ethylhexyl phthalate (DEHP) and its substitute 1,2-cyclohexane dicarboxylic acid diisononyl ester (DINCH) are widely used as plasticizers but may have adverse health effects. Via hydrolysis of one of the two ester bonds in the human body, DEHP and DINCH form the monoesters MEHP and MINCH, respectively. Previous studies demonstrated binding of these metabolites to PPARγ and the induction of adipogenesis via this pathway. Detailed structural understanding of how these metabolites interact with PPARγ and thereby affect human health is lacking until now. We therefore characterized the binding modes of MINCH and MEHP to the ligand binding domain of PPARγ by X-ray crystallography and molecular dynamics (MD) simulations. Both compounds bind to the activating function-2 (AF-2) binding site via an interaction of the free carboxylates with the histidines 323 and 449, tyrosine 473 and serine 289. The alkyl chains form hydrophobic interactions with the tunnel next to cysteine 285. These binding modes are generally stable as demonstrated by the MD simulations and they resemble the complexation of fatty acids and their metabolites to the AF-2 site of PPARγ. Similar to the situation for these natural PPARγ agonists, the interaction of the free carboxylate groups of MEHP and MINCH with tyrosine 473 and surrounding residues stabilizes the AF-2 helix in the upward conformation. This state promotes binding of coactivator proteins and thus formation of the active complex for transcription of the specific target genes. Moreover, a comparison of the residues involved in binding of the plasticizer metabolites in vertebrate PPARγ orthologs shows that these compounds likely have similar effects in other species.

PubMed: 36841188
DOI: 10.1016/j.envint.2023.107822

Experimental method

X-RAY DIFFRACTION (2.18 Å)