Low-Resolution Molecular Models Reveal the Oligomeric State of the PPAR and the Conformational Organization of Its Domains in SolutionReport as inadecuate




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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.



Author: Amanda Bernardes , Fernanda A. H. Batista , Mario de Oliveira Neto, Ana Carolina M. Figueira, Paul Webb, Daniel Saidemberg, Mario

Source: http://plos.srce.hr/



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