Matches in SemOpenAlex for { <https://semopenalex.org/work/W4321350639> ?p ?o ?g. }
- W4321350639 endingPage "107822" @default.
- W4321350639 startingPage "107822" @default.
- W4321350639 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." @default.
- W4321350639 created "2023-02-20" @default.
- W4321350639 creator A5011853443 @default.
- W4321350639 creator A5018338280 @default.
- W4321350639 creator A5035814975 @default.
- W4321350639 creator A5060414551 @default.
- W4321350639 date "2023-03-01" @default.
- W4321350639 modified "2023-09-28" @default.
- W4321350639 title "Structural basis of the activation of PPARγ by the plasticizer metabolites MEHP and MINCH" @default.
- W4321350639 cites W1855128821 @default.
- W4321350639 cites W1973318863 @default.
- W4321350639 cites W1979232857 @default.
- W4321350639 cites W1983254116 @default.
- W4321350639 cites W1985018784 @default.
- W4321350639 cites W1994612860 @default.
- W4321350639 cites W2002519246 @default.
- W4321350639 cites W2005562492 @default.
- W4321350639 cites W2015275965 @default.
- W4321350639 cites W2015688756 @default.
- W4321350639 cites W2018764435 @default.
- W4321350639 cites W2023955385 @default.
- W4321350639 cites W2029667189 @default.
- W4321350639 cites W2038531680 @default.
- W4321350639 cites W2050321497 @default.
- W4321350639 cites W2050717908 @default.
- W4321350639 cites W2056057915 @default.
- W4321350639 cites W2056250382 @default.
- W4321350639 cites W2060363772 @default.
- W4321350639 cites W2066619221 @default.
- W4321350639 cites W2067174909 @default.
- W4321350639 cites W2068576828 @default.
- W4321350639 cites W2069663555 @default.
- W4321350639 cites W2071684520 @default.
- W4321350639 cites W2073482601 @default.
- W4321350639 cites W2078297786 @default.
- W4321350639 cites W2096787550 @default.
- W4321350639 cites W2097127734 @default.
- W4321350639 cites W2098167941 @default.
- W4321350639 cites W2100408829 @default.
- W4321350639 cites W2104221349 @default.
- W4321350639 cites W2106140689 @default.
- W4321350639 cites W2107406242 @default.
- W4321350639 cites W2113456624 @default.
- W4321350639 cites W2116099439 @default.
- W4321350639 cites W2116513829 @default.
- W4321350639 cites W2117009957 @default.
- W4321350639 cites W2117035262 @default.
- W4321350639 cites W2117897211 @default.
- W4321350639 cites W2117923938 @default.
- W4321350639 cites W2118233996 @default.
- W4321350639 cites W2119489910 @default.
- W4321350639 cites W2124026197 @default.
- W4321350639 cites W2136703636 @default.
- W4321350639 cites W2145928638 @default.
- W4321350639 cites W2146131821 @default.
- W4321350639 cites W2147596285 @default.
- W4321350639 cites W2150022994 @default.
- W4321350639 cites W2150444353 @default.
- W4321350639 cites W2154197653 @default.
- W4321350639 cites W2155797089 @default.
- W4321350639 cites W2159010139 @default.
- W4321350639 cites W2160907977 @default.
- W4321350639 cites W2163417923 @default.
- W4321350639 cites W2168240189 @default.
- W4321350639 cites W2170831952 @default.
- W4321350639 cites W2182545443 @default.
- W4321350639 cites W2218002617 @default.
- W4321350639 cites W2226687342 @default.
- W4321350639 cites W2298055661 @default.
- W4321350639 cites W2400270442 @default.
- W4321350639 cites W2619745907 @default.
- W4321350639 cites W2769250691 @default.
- W4321350639 cites W2794079431 @default.
- W4321350639 cites W2886284196 @default.
- W4321350639 cites W2891247774 @default.
- W4321350639 cites W2897865525 @default.
- W4321350639 cites W2900981302 @default.
- W4321350639 cites W2910333255 @default.
- W4321350639 cites W2912709516 @default.
- W4321350639 cites W2913241666 @default.
- W4321350639 cites W2966844859 @default.
- W4321350639 cites W2980581744 @default.
- W4321350639 cites W2989052455 @default.
- W4321350639 cites W3001474993 @default.
- W4321350639 cites W3013348799 @default.
- W4321350639 cites W3028710516 @default.
- W4321350639 cites W3177828909 @default.
- W4321350639 cites W3198280675 @default.
- W4321350639 cites W3211795435 @default.
- W4321350639 cites W4229065890 @default.
- W4321350639 cites W4237790777 @default.
- W4321350639 cites W4248872320 @default.
- W4321350639 cites W4250937525 @default.
- W4321350639 cites W2471115708 @default.
- W4321350639 doi "https://doi.org/10.1016/j.envint.2023.107822" @default.
- W4321350639 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/36841188" @default.
- W4321350639 hasPublicationYear "2023" @default.
- W4321350639 type Work @default.