Low-resolution molecular models reveal the oligomeric state of the PPAR and the conformational organization of its domains in solution.

The peroxisome proliferator-activated receptors (PPARs) regulate genes involved in lipid and carbohydrate metabolism, and are targets of drugs approved for human use. Whereas the crystallographic structure of the complex of full length PPARγ and RXRα is known, structural alterations induced by heter...

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Autores principales:	Amanda Bernardes, Fernanda A H Batista, Mario de Oliveira Neto, Ana Carolina M Figueira, Paul Webb, Daniel Saidemberg, Mario S Palma, Igor Polikarpov
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2012
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/b6f23f6bd133454aab9123c2c9c1175e
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spelling	oai:doaj.org-article:b6f23f6bd133454aab9123c2c9c1175e2021-11-18T07:27:15ZLow-resolution molecular models reveal the oligomeric state of the PPAR and the conformational organization of its domains in solution.1932-620310.1371/journal.pone.0031852https://doaj.org/article/b6f23f6bd133454aab9123c2c9c1175e2012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22363753/?tool=EBIhttps://doaj.org/toc/1932-6203The peroxisome proliferator-activated receptors (PPARs) regulate genes involved in lipid and carbohydrate metabolism, and are targets of drugs approved for human use. Whereas the crystallographic structure of the complex of full length PPARγ and RXRα is known, structural alterations induced by heterodimer formation and DNA contacts are not well understood. Herein, we report a small-angle X-ray scattering analysis of the oligomeric state of hPPARγ alone and in the presence of retinoid X receptor (RXR). The results reveal that, in contrast with other studied nuclear receptors, which predominantly form dimers in solution, hPPARγ remains in the monomeric form by itself but forms heterodimers with hRXRα. The low-resolution models of hPPARγ/RXRα complexes predict significant changes in opening angle between heterodimerization partners (LBD) and extended and asymmetric shape of the dimer (LBD-DBD) as compared with X-ray structure of the full-length receptor bound to DNA. These differences between our SAXS models and the high-resolution crystallographic structure might suggest that there are different conformations of functional heterodimer complex in solution. Accordingly, hydrogen/deuterium exchange experiments reveal that the heterodimer binding to DNA promotes more compact and less solvent-accessible conformation of the receptor complex.Amanda BernardesFernanda A H BatistaMario de Oliveira NetoAna Carolina M FigueiraPaul WebbDaniel SaidembergMario S PalmaIgor PolikarpovPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 7, Iss 2, p e31852 (2012)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Amanda Bernardes Fernanda A H Batista Mario de Oliveira Neto Ana Carolina M Figueira Paul Webb Daniel Saidemberg Mario S Palma Igor Polikarpov Low-resolution molecular models reveal the oligomeric state of the PPAR and the conformational organization of its domains in solution.
description	The peroxisome proliferator-activated receptors (PPARs) regulate genes involved in lipid and carbohydrate metabolism, and are targets of drugs approved for human use. Whereas the crystallographic structure of the complex of full length PPARγ and RXRα is known, structural alterations induced by heterodimer formation and DNA contacts are not well understood. Herein, we report a small-angle X-ray scattering analysis of the oligomeric state of hPPARγ alone and in the presence of retinoid X receptor (RXR). The results reveal that, in contrast with other studied nuclear receptors, which predominantly form dimers in solution, hPPARγ remains in the monomeric form by itself but forms heterodimers with hRXRα. The low-resolution models of hPPARγ/RXRα complexes predict significant changes in opening angle between heterodimerization partners (LBD) and extended and asymmetric shape of the dimer (LBD-DBD) as compared with X-ray structure of the full-length receptor bound to DNA. These differences between our SAXS models and the high-resolution crystallographic structure might suggest that there are different conformations of functional heterodimer complex in solution. Accordingly, hydrogen/deuterium exchange experiments reveal that the heterodimer binding to DNA promotes more compact and less solvent-accessible conformation of the receptor complex.
format	article
author	Amanda Bernardes Fernanda A H Batista Mario de Oliveira Neto Ana Carolina M Figueira Paul Webb Daniel Saidemberg Mario S Palma Igor Polikarpov
author_facet	Amanda Bernardes Fernanda A H Batista Mario de Oliveira Neto Ana Carolina M Figueira Paul Webb Daniel Saidemberg Mario S Palma Igor Polikarpov
author_sort	Amanda Bernardes
title	Low-resolution molecular models reveal the oligomeric state of the PPAR and the conformational organization of its domains in solution.
title_short	Low-resolution molecular models reveal the oligomeric state of the PPAR and the conformational organization of its domains in solution.
title_full	Low-resolution molecular models reveal the oligomeric state of the PPAR and the conformational organization of its domains in solution.
title_fullStr	Low-resolution molecular models reveal the oligomeric state of the PPAR and the conformational organization of its domains in solution.
title_full_unstemmed	Low-resolution molecular models reveal the oligomeric state of the PPAR and the conformational organization of its domains in solution.
title_sort	low-resolution molecular models reveal the oligomeric state of the ppar and the conformational organization of its domains in solution.
publisher	Public Library of Science (PLoS)
publishDate	2012
url	https://doaj.org/article/b6f23f6bd133454aab9123c2c9c1175e
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Low-resolution molecular models reveal the oligomeric state of the PPAR and the conformational organization of its domains in solution.

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